Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof

ABSTRACT

Amino, amido, and heterocyclic compounds are disclosed. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diabetes complications, inflammation, and neurodegeneration, obesity, cancer, ischemia/reperfusion injury, cardiovascular disease and other diseases related to RAGE activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 USC §119(e) from U.S.Provisional Application Ser. Nos. 61/885,176 and 61/885,183, which werefiled Oct. 1, 2013, each of which applications is herein specificallyincorporated by reference in its entirety.

GOVERNMENTAL SUPPORT

The research leading to the present invention was funded in part by NIHgrant 1R24DK103032-01. The United States government has certain rightsin the invention.

FIELD OF THE INVENTION

This invention relates to amino, amido, and heterocyclic compoundscapable of modulating the receptor for advanced glycation end products(RAGE) activity. Specifically, this invention relates to amino, amido,and heterocyclic compounds capable of modulating the interaction of RAGEand its ligands, and uses of such compounds to treat diseases orconditions related to RAGE activity. More particularly, the amino,amido, and heterocyclic compounds may be used to treat diabetescomplications, inflammation, and neurodegeneration, obesity, cancer,ischemia/reperfusion injury, cardiovascular disease and other diseasesrelated to RAGE activity. Also encompassed herein, are compositions ofamino, amido, and heterocyclic compounds, pharmaceutical compositions ofamino, amido, and heterocyclic compounds, and assays and methods forusing same to identify compounds capable of modulating RAGE activity.

BACKGROUND OF THE INVENTION

The receptor for advanced glycation end products (RAGE) is a multiligandcell surface macromolecule that plays a central role in the etiology ofdiabetes complications, obesity, inflammation, cancer andneurodegeneration. The cytoplasmic domain of RAGE, C terminal RAGE orctRAGE (RAGE tail) is critical for RAGE-dependent signal transduction.As the most membrane proximal event, mDia1 binds to RAGE and isessential for RAGE ligand-stimulated phosphorylation of kinases andcellular properties such as AKT and cell proliferation/migration ofsmooth muscle cells; activation of cdc42 and rac 1 in smooth musclecells and transformed cells; and upregulation of early growth response 1in hypoxic macrophages, as examples. RAGE contains an unusual α-turnthat mediates the mDia1-RAGE interaction and is required for RAGEdependent signaling (Shekhtman et al, J. Bio. Chem., 2012, 287(7)5133-5142).

RAGE-ligand interactions evoke central changes in cellular propertiesincluding stimulation of cellular migration and proliferation andleading to such pathological conditions as diabetes and itscomplications, Alzheimer's disease, inflammation and cancers. RAGE alsoplays a pivotal role in the atherosclerotic process (Schmidt, et al.(1999) Circ Res 84, 489-497). Thus, inhibition of the RAGE activity isdesirable for treatment of these conditions.

US application publication, US2012/0088778 discloses azole derivativesas modulators of the interaction of RAGE and its ligands or RAGEactivity. The azole compounds are reported to be useful for treatment ofdiseases including acute and chronic inflammation, the development ofdiabetic late complications, and others.

US application publication, US2010/0254983 discloses methods fortreating obesity using antagonists of binding of RAGE ligands to RAGE.

US application publication, US2010/0119512 discloses carboxamidederivatives as modulators of the interaction of RAGE and its ligands orRAGE activity.

U.S. Pat. No. 7,361,678 discloses composition of 3,5-diphenyl-imidazolederivatives as modulators of the interaction of RAGE and its ligands orRAGE activity.

International application publication, WO2007/089616, discloses tertiaryamides as modulators of the interaction of RAGE and its ligands or RAGEactivity.

US application publication, US2010/0249038, discloses novel peptides asantagonists of RAGE.

Many or most of the ligands disclosed in the above applications bind tothe extracellular domain of RAGE.

In view of the above, a need exists for therapeutic agents, andcorresponding pharmaceutical compositions and related methods oftreatment that address conditions causally related to RAGE activity, andit is toward the fulfillment and satisfaction of that need, that thepresent invention is directed.

SUMMARY OF THE INVENTION

The present invention provides amino, amido, and heterocyclic compoundscapable of modulating the receptor for advanced glycation end products(RAGE) activity.

Specifically, the invention provides amino, amido, and heterocycliccompounds capable of modulating the interaction of RAGE and its ligands,and uses of such compounds to treat diseases or conditions related toRAGE activity.

More specifically, the invention provides amino, amido, and heterocycliccompounds capable of modulating the interaction of RAGE and its ligandsbinding to the intracellular domain of the RAGE, and uses of suchcompounds to treat diseases or conditions related to RAGE activity.

In one aspect, the present invention provides a method for preventing,treating or ameliorating in a mammal a disease or condition that iscausally related to RAGE activity in vivo, which comprises administeringto the mammal an effective disease-treating or condition-treating amountof a compound according to formula A-Ia or A-Ib:

-   -   wherein        -   L¹ is —NH—, —CH₂—NH—, —CH₂—CH₂—NH—, —CO—NH— or            —CO—NH-L²-CO—NH—; and    -   Cy is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl; or        -   L¹ is a bond and Cy is

-   -   -   R¹ is H, substituted or unsubstituted C₁-C₆ alkyl,            substituted or unsubstituted C₁-C₆ alkoxy, or halo;        -   each R² is independently selected from OH, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted acyl, substituted or            unsubstituted acylamino, substituted or unsubstituted            alkylamino, substituted or unsubstituted alkythio,            substituted or unsubstituted alkoxycarbonyl, substituted or            unsubstituted alkylarylamino, substituted or unsubstituted            amino, substituted or unsubstituted arylalkyl, sulfo,            substituted sulfo, substituted sulfonyl, substituted            sulfinyl, substituted sulfanyl, substituted or unsubstituted            aminosulfonyl, substituted or unsubstituted alkylsulfonyl,            substituted or unsubstituted arylsulfonyl, azido,            substituted or unsubstituted carbamoyl, carboxyl, cyano,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted heterocycloalkyl,            substituted or unsubstituted dialkylamino, halo, nitro, and            thiol; or two adjacent R¹ and R² groups may join together to            form a substituted or unsubstituted carbocyclic or            heterocyclic ring;        -   R³ is H, or substituted or unsubstituted C₁-C₆ alkyl;        -   the subscript n is 0, 1, 2, or 3;        -   L² is C₁-C₃ alkylene;        -   X is CH or N; Y is O or NR⁵;        -   R⁴ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl,        -   substituted or unsubstituted aryl, or substituted or            unsubstituted heteroaryl;        -   R⁵ is H or substituted or unsubstituted alkyl; and *            represents an attachment point;

    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;

    -   and stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-II, A-III, A-IV, A-V, A-VI, A-VII:

wherein Cy, X, Y, R¹, R², R⁴, and n are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ib, thecompound is according to formula A-V:

wherein Cy, X, Y, R¹, R², R³, and n are as described for formula A-Ib.

In one particular embodiment, with respect to the compound of formulaA-Ia or A-Ib, the compound is according to formula A-XIVa, A-XIVb,A-XIVc, A-XIVd, A-XV, A-XVIb, or A-XXb.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-I′:

wherein each A¹, A², A³, A⁴, X, Z, R¹, R², and R^(3a) are as describedherein.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-I:

-   -   wherein    -   each A¹, A², A³, A⁴, B¹, B², B³, and B⁴, is independently CR⁴ or        N; provided that only 1 or 2 of A¹, A², A³, and A⁴ are N, and        only 1 or 2 of B¹, B², B³, and B⁴ are N at any one time;    -   X is CR^(5a) or N; X is CR^(5b) or N;    -   R¹ is hydroxy, substituted hydroxyl, amino, or substituted        amino;    -   R² is H, alkyl or aryl;    -   each R^(3a) and R^(3b) is independently H, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, halo, or cyano;    -   each R⁴ is independently selected from H, OH, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted acyl, substituted or unsubstituted        acylamino, substituted or unsubstituted alkylamino, substituted        or unsubstituted alkythio, substituted or unsubstituted        alkoxycarbonyl, substituted or unsubstituted alkylarylamino,        substituted or unsubstituted amino, substituted or unsubstituted        arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,        substituted sulfinyl, substituted sulfanyl, substituted or        unsubstituted aminosulfonyl, substituted or unsubstituted        alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted cycloalkyl, substituted        or unsubstituted heterocycloalkyl, substituted or unsubstituted        dialkylamino, halo, nitro, and thiol;    -   R^(5a) is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, halo, or cyano; or R^(5a) and R^(3a) may        join together to form a substituted or unsubstituted carbocyclic        or heterocyclic ring;    -   R^(5b) is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, halo, or cyano; or R^(5b) and R^(3b) may        join together to form a substituted or unsubstituted carbocyclic        or heterocyclic ring; and each of the subscript m and n is        independently 1, 2, or 3;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-II:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-III:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-IV:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-V:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-VI:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XId:

In one embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XIIIa:

In one particular embodiment, the compound is according to formula B-II,B-III, B-IV, B-V, or B-VI.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising amide compounds of the invention, and apharmaceutical carrier, excipient or diluent. In this aspect of theinvention, the pharmaceutical composition can comprise one or more ofthe compounds described herein. Moreover, the compounds of the presentinvention useful in the pharmaceutical compositions and treatmentmethods disclosed herein are all pharmaceutically acceptable as preparedand used.

In a further aspect, this invention provides a method of treating amammal susceptible to or afflicted with a condition from among thoselisted herein, and particularly, such condition as may be associatedwith RAGE activity. Such conditions include, without limitation,diabetes and its complications, impaired wound healing, peripheralvascular disease and associated complications, obesity, Alzheimer'sdisease, cancers, arthritis, nephropathy, acute and chronicinflammation, retinopathy, atherosclerosis, cardiovascular disease,erectile dysfunction, tumor invasion and metastases, neuropathy, cardio-and cerebrovascular ischemia/reperfusion injury, heart attack, stroke,myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis,pneumonia, infection, liver injury, liver damage, Amyotrophic lateralsclerosis, neuropathy infection, allergy, asthma, organ damage frompollutants, amyloidoses asthma, pollution-associated tissue damage, skindisorders, colitis, skin aging, and lupus.

Also encompassed herein is a method for inhibiting RAGE activity in asubject (e.g., a mammal) in need thereof, the method comprisingadministering to the subject an effective RAGE-inhibiting amount of acompound as described herein so as to reduce/inhibit RAGE activity inthe subject. Such compounds may be a compound according to formula A-Iaor A-Ib as described herein. In a particular embodiment thereof, withrespect to the compound of formula A-Ia, the compound is according toformula A-II, A-III, A-IV, A-V, A-VI, A-VII. In a particular embodimentthereof, with respect to the compound of formula A-Ib, the compound isaccording to formula A-V. In a particular embodiment, with respect tothe compound of formula A-Ia or A-Ib, the compound is according toformula A-XIVa, A-XIVb, A-XIVc, A-XIVd, A-XV, A-XVIb, or A-XXb. Inanother particular embodiment, with respect to the compound of formulaA-Ia or A-Ib, the compound is according to formula A-XIVa, A-XIVb,A-XIVc, A-XIVd, A-XV, A-XVIb, or A-XXb. Such compounds may, furthermore,be a compound according to formula B-I′; a compound according to formulaB-I; a compound according to formula B-II; a compound according toformula B-III; a compound according to formula B-IV; a compoundaccording to formula B-V; or a compound according to formula B-VI asdescribed herein. In a particular embodiment, with respect to thecompound of formula B-I, the compound is according to formula B-XId. Inanother particular embodiment, with respect to the compound of formulaB-I, the compound is according to formula B-XIIIa. In yet anotherparticular embodiment, the compound is according to formula B-II, B-III,B-IV, B-V, or B-VI.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows RAGE tail Fluorescence Titration data for Compound CB-1.

FIG. 2 shows a flow chart for Secondary screening using NMRspectroscopy.

FIG. 3 shows NMR spectrum of RAGE tail in complex with compound CB-6.Red—overlay of ¹⁵N-HSQC spectra of free (red). Black—CB-6 bound [U—¹⁵N]RAGE tail. Asteric—New peaks or peaks that undergo significant shifts orpeak broadening (labeled by corresponding amino acid residue numbers).

FIG. 4 shows RAGE tail Fluorescence Titration data for Compound CB-2(formula B-II).

FIG. 5 shows RAGE tail Fluorescence Titration data for Compound CB-4(formula B-XIIIa).

FIG. 6 shows the NMR spectrum of RAGE tail in complex with compoundCB-3. Red—overlay of ¹⁵N-HSQC spectra of free (red). Black—CB-3 bound[U—¹⁵N] RAGE tail. Asteric—New peaks or peaks that undergo significantshifts or peak broadening (labeled by corresponding amino acid residuenumbers).

FIG. 7 presents test compound dissociation constants for CB-1 to CB-14.

FIG. 8 shows the effects of CB-1 to CB-14 on murine smooth muscle cellmigration.

FIG. 9 shows the effects of CB-1 to CB-14 on human smooth muscle cellmigration.

FIG. 10 shows the effects of compounds CB-1 to CB-14 on the inflammatoryresponse in the context of delayed type hypersensitivity mediatedinflammation in mice.

DETAILED DESCRIPTION OF THE INVENTION

In that RAGE and its ligands have been positioned at the center ofchronic inflammation and it is, moreover, understood that chronicinflammation contributes significantly to the pathogenesis of diversedisorders, the compounds described herein are envisioned as useful forthe treatment of diseases wherein inflammation plays a pathological roleand RAGE contributes thereto. Such diseases and disorders includeinflammatory bowel disease, delayed-type hypersensitivity,atherosclerosis, the complications of diabetes (including neuropathy andatherosclerosis), asthma, myocardial ischemia, atherosclerosis, aneurysmformation, doxorubicin toxicity, acetaminophen toxicity,neurodegeneration, hyperlipidemia, preeclampsia, rheumatoid arthritis,pulmonary fibrosis, and Alzheimer's Disease. See, for example, Hofmannet al. (1999, Cell 97:889-901); Akirav et al. (2014, PLoS One 9:e95678);Johnson et al. (2014, EJNMMI Res 4:26); Tekabe et al. (2014, Int J MolImaging 2014:695391); Song et al. (2014, Diabetes 63:1948-1965); Ullahet al. (2014, J Allergy Clin Immunol 134:440-450); Juranek et al. (2013,Brain Behav 3:701-709); Daffu et al. (2013, Int J Mol Sci14:19891-19910); Manigrasso et al. (2014, Trends Endocrinol Metab25:15-22); Tekabe et al. (2013, EJNMMi Res 3:37); Rai et al. (2012, JExp Med 209:2339-2350); Ramasamy et al. (2012, Vascular Pharmacol 57:160-167); Arumugam et al. (2012, Clin Canc Res 18:4356-4364); the entirecontent of each of which is incorporated herein by reference.

Definitions

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.It should also be understood that any of the moieties defined forthbelow may be substituted with a variety of substituents, and that therespective definitions are intended to include such substituted moietieswithin their scope. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” refers to a radical —NR²¹C(O)R²², where R²¹ is hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl and R²² is hydrogen, alkyl, alkoxy,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroarylor heteroarylalkyl, as defined herein. Representative examples include,but are not limited to, formylamino, acetylamino,cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino,benzylcarbonylamino and the like.

“Acyloxy” refers to the group —OC(O)R²³ where R²³ is hydrogen, alkyl,aryl or cycloalkyl.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkoxy” refers to the group —OR²⁴ where R²⁴ is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkoxycarbonylamino” refers to the group —NR²⁵C(O)OR²⁶, where R²⁵ ishydrogen, alkyl, aryl or cycloalkyl, and R²⁶ is alkyl or cycloalkyl.

“Alkyl” refers to monovalent saturated alkane radical groupsparticularly having up to about 11 carbon atoms, more particularly as alower alkyl, from 1 to 8 carbon atoms and still more particularly, from1 to 6 carbon atoms. The hydrocarbon chain may be eitherstraight-chained or branched. This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl,n-hexyl, n-octyl, tert-octyl and the like. The term “lower alkyl” refersto alkyl groups having 1 to 6 carbon atoms. The term “alkyl” alsoincludes “cycloalkyls” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkyl group having 1or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂—, andaryl-S(O)₂—.

“Alkylene” refers to divalent saturated alkene radical groups having 1to 11 carbon atoms and more particularly 1 to 6 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas methylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8carbon atoms, and more particularly, from 2 to 6 carbon atoms, which canbe straight-chained or branched and having at least 1 and particularlyfrom 1 to 2 sites of olefinic unsaturation. Particular alkenyl groupsinclude ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), isopropenyl(—C(CH₃)═CH₂), vinyl and substituted vinyl, and the like.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having up to about 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofolefinic unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH₂— and—C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically or alkynically unsaturatedhydrocarbyl groups particularly having 2 to 11 carbon atoms, and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude acetylenic, ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” or “acyl” as used herein refers to the group R²⁷—C(O)—, whereR²⁷ is hydrogen or alkyl as defined above.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted with 1 or more substituents, for instance from1 to 5 substituents, particularly 1 to 3 substituents, selected from thegroup consisting of acyl, acylamino, acyloxy, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substitutedalkyl, alkynyl, substituted alkynyl, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring.

“Alkaryl” refers to an aryl group, as defined above, substituted withone or more alkyl groups, as defined above.

“Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above,substituted with one or more aryl groups, as defined above.

“Aryloxy” refers to —O-aryl groups wherein “aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR²⁸R²⁹, wherein each of R²⁸ andR²⁹ are independently selected from hydrogen and alkyl.

“Arylamino” refers to the group aryl-NR³⁰R³¹, wherein each of R³⁰ andR³¹ are independently selected from hydrogen, aryl and heteroaryl.

“Alkoxyamino” refers to a radical —N(H)OR³² where R³² represents analkyl or cycloalkyl group as defined herein.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkylarylamino” refers to a radical —NR³³R³⁴ where R³³ represents analkyl or cycloalkyl group and R³⁴ is an aryl as defined herein.

“Alkylsulfonyl” refers to a radical —S(O)₂R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(O)R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R³⁶)₂where each R³⁶ is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,and where both R groups are joined to form an alkylene group. When bothR groups are hydrogen, —N(R³⁶)₂ is an amino group.

“Aminocarbonyl” refers to the group —C(O)NR³⁷R³⁷ where each R³⁷ isindependently hydrogen, alkyl, aryl and cycloalkyl, or where the R³⁷groups are joined to form an alkylene group.

“Aminocarbonylamino” refers to the group —NR³⁸C(O)NR³⁸R³⁸ where each R³⁸is independently hydrogen, alkyl, aryl or cycloalkyl, or where two Rgroups are joined to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC(O)NR³⁹R³⁹ where each R³⁹ isindependently hydrogen, alkyl, aryl or cycloalky, or where the R groupsare joined to form an alkylene group.

“Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein.

“Arylamino” means a radical —NHR⁴⁰ where R⁴⁰ represents an aryl group asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl is asdefined herein.

“Arylsulfonyl” refers to a radical —S(O)₂R⁴¹ where R⁴¹ is an aryl orheteroaryl group as defined herein.

“Azido” refers to the radical —N₃.

“Bicycloaryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent bicycloaromatic ring system. Typical bicycloaryl groups include,but are not limited to, groups derived from indane, indene, naphthalene,tetrahydronaphthalene, and the like. Particularly, an aryl groupcomprises from 8 to 11 carbon atoms.

“Bicycloheteroaryl” refers to a monovalent bicycloheteroaromatic groupderived by the removal of one hydrogen atom from a single atom of aparent bicycloheteroaromatic ring system. Typical bicycloheteroarylgroups include, but are not limited to, groups derived from benzofuran,benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline,phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole,naphthyridine, benzoxadiazole, pteridine, purine, benzopyran,benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine,quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline,and the like. Preferably, the bicycloheteroaryl group is between 9-11membered bicycloheteroaryl, with 5-10 membered heteroaryl beingparticularly preferred. Particular bicycloheteroaryl groups are thosederived from benzothiophene, benzofuran, benzothiazole, indole,quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” refers to the radical —C(O)N(R⁴²)₂ where each R⁴² group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Carboxyamino” refers to the radical —N(H)C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR⁴³ where R⁴³ is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having 1 or more substituents, for instance from 1 to5 substituents, and particularly from 1 to 3 substituents, selected fromthe group consisting of acyl, acylamino, acyloxy, alkoxy, substitutedalkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NR⁴⁴R⁴⁵ where R⁴⁴ and R⁴⁵ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Preferredhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R⁴⁶, —O—, ═O,—OR⁴⁶, —SR⁴⁶, —S⁻, ═S, —NR⁴⁶R⁴⁷, ═NR⁴⁶, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O—, —S(O)₂OH, —S(O)₂R⁴⁶, —OS(O₂)O⁻,—OS(O)₂R⁴⁶, —P(O)(O⁻)₂, —P(O)(OR⁴⁶)(O⁻), —OP(O)(OR⁴⁶)(OR⁴⁷), —C(O)R⁴⁶,—C(S)R⁴⁶, —C(O)OR⁴⁶, —C(O)NR⁴⁶R⁴⁷, —C(O)O—, —C(S)OR⁴⁶, —NR⁴⁸C(O)NR⁴⁶R⁴⁷,—NR⁴⁸C(S)NR⁴⁶R⁴⁷, NR⁴⁹C(NR⁴⁸)NR⁴⁶R⁴⁷ and —C(NR⁴⁸)NR⁴⁶R⁴⁷, where each Xis independently a halogen; each R⁴⁶, R⁴⁷, R⁴⁸ and R⁴⁹ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl,substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR⁵⁰R⁵¹, —C(O)R⁵⁰ or —S(O)₂R⁵⁰ or optionally R⁵⁰ andR⁵¹ together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R⁵⁰ and R⁵¹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedalkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

Examples of representative substituted aryls include the following

In these formulae one of R⁵² and R⁵³ may be hydrogen and at least one ofR⁵² and R⁵³ is each independently selected from alkyl, alkenyl, alkynyl,cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, heteroarylamino, NR⁵⁴COR⁵⁵, NR⁵⁴SOR⁵⁵, NR⁵⁴SO₂R⁵⁷, COOalkyl,COOaryl, CONR⁵⁴R⁵⁵, CONR⁵⁴OR⁵⁵, NR⁵⁴R⁵⁵, SO₂NR⁵⁴R⁵⁵, S-alkyl, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵² and R⁵³ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O or S. R⁵⁴, R⁵⁵, and R⁵⁶ are independently hydrogen, alkyl, alkenyl,alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substitutedaryl, heteroaryl, substituted or hetero alkyl or the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-15 membered heteroaryl, with 5-10 membered heteroarylbeing particularly preferred. Particular heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁵⁸, O, and S; and R⁵⁸ isindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,heteroaryl, heteroalkyl or the like.

As used herein, the term “cycloheteroalkyl” refers to a stableheterocyclic non-aromatic ring and fused rings containing one or moreheteroatoms independently selected from N, O and S. A fused heterocyclicring system may include carbocyclic rings and need only include oneheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl,and are shown in the following illustrative examples:

wherein each X is selected from CR⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from NR⁵⁸, O and S; and R⁵⁸ is independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.These cycloheteroalkyl rings may be optionally substituted with one ormore groups selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Substitutinggroups include carbonyl or thiocarbonyl which provide, for example,lactam and urea derivatives.

Examples of representative cycloheteroalkenyls include the following:

wherein each X is selected from CR⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from carbonyl, N, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

Examples of representative aryl having hetero atoms containingsubstitution include the following:

wherein each X is selected from C—R⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from carbonyl, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

“Hetero substituent” refers to a halo, O, S or N atom-containingfunctionality that may be present as an R⁴ in a R⁴C group present assubstituents directly on A, B, W, Y or Z of the compounds of thisinvention or may be present as a substituent in the “substituted” aryland aliphatic groups present in the compounds.

Examples of hetero substituents include:

-halo,

—NO₂, —NH₂, —NHR⁵⁹, —N(R⁵⁹)₂,

—NRCOR, —NR⁵⁹SOR⁵⁹, —NR⁵⁹SO₂R⁵⁹, OH, CN,

—CO₂H,

—R⁵⁹—OH, —O—R⁵⁹, —COOR⁵⁹,

—CON(R⁵⁹) 2, —CONROR⁵⁹,

—SO₃H, —R⁵⁹—S, —SO₂N(R⁵⁹)₂,

—S(O)R⁵⁹, —S(O)₂R⁵⁹

wherein each R⁵⁹ is independently an aryl or aliphatic, optionally withsubstitution. Among hetero substituents containing R⁵⁹ groups,preference is given to those materials having aryl and alkyl R⁵⁹ groupsas defined herein. Preferred hetero substituents are those listed above.

“Hydrogen bond donor” group refers to a group containing O—H, or N—Hfunctionality. Examples of “hydrogen bond donor” groups include —OH,—NH₂, and —NH—R^(59a) and wherein R^(59a) is alkyl, cycloalkyl, aryl, orheteroaryl.

“Dihydroxyphosphoryl” refers to the radical —PO(OH)₂.

“Substituted dihydroxyphosphoryl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to adihydroxyphosphoryl radical wherein one or both of the hydroxyl groupsare substituted. Suitable substituents are described in detail below.

“Aminohydroxyphosphoryl” refers to the radical —PO(OH)NH₂.

“Substituted aminohydroxyphosphoryl” includes those groups recited inthe definition of “substituted” herein, and particularly refers to anaminohydroxyphosphoryl wherein the amino group is substituted with oneor two substituents. Suitable substituents are described in detailbelow. In certain embodiments, the hydroxyl group can also besubstituted.

“Thioalkoxy” refers to the group —SR⁶⁰ where R⁶⁰ is alkyl.

“Substituted thioalkoxy” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a thioalkoxy grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein.

“Sulfonyl” refers to the divalent radical —S(O₂)—. “Substitutedsulfonyl” refers to a radical such as R⁶¹—(O₂)S— wherein R⁶¹ is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O₂)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R⁶² ₂N(O₂)S— wherein each R⁶²is independently any substituent described herein.

“Sulfone” refers to the group —SO₂R⁶³. In particular embodiments, R⁶³ isselected from H, lower alkyl, alkyl, aryl and heteroaryl.

“Thioaryloxy” refers to the group —SR⁶⁴ where R⁶⁴ is aryl.

“Thioketo” refers to the group ═S.

“Thiol” refers to the group —SH.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

“Pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to a non toxic, acceptablecationic counter-ion of an acidic functional group. Such cations areexemplified by sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium cations, and the like.

“Pharmaceutically acceptable vehicle” or “Pharmaceutically acceptablecarrier” refer to a pharmaceutically acceptable diluent, apharmaceutically acceptable adjuvant, a pharmaceutically acceptableexcipient, or a combination of any of the foregoing with which acomposition provided by the present disclosure may be administered to apatient and which does not destroy the pharmacological activity thereofand which is non-toxic when administered in doses sufficient to providea therapeutically effective amount of the composition. In addition tothe adjuvants, excipients and diluents known to one skilled in the art,the vehicle or carrier includes nanoparticles of organic and inorganicnature.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. Conventional solvents includewater, ethanol, acetic acid and the like. The compounds of the inventionmay be prepared e.g. in crystalline form and may be solvated orhydrated. Suitable solvates include pharmaceutically acceptablesolvates, such as hydrates, and further include both stoichiometricsolvates and non-stoichiometric solvates.

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.

As used herein, the term “operably linked” refers to a regulatorysequence capable of mediating the expression of a coding sequence andwhich is placed in a DNA molecule (e.g., an expression vector) in anappropriate position relative to the coding sequence so as to effectexpression of the coding sequence. This same definition is sometimesapplied to the arrangement of coding sequences and transcription controlelements (e.g. promoters, enhancers, and termination elements) in anexpression vector. This definition is also sometimes applied to thearrangement of nucleic acid sequences of a first and a second nucleicacid molecule wherein a hybrid nucleic acid molecule is generated.

A “vector” is a replicon, such as a plasmid, cosmid, bacmid, phage orvirus, to which another genetic sequence or element (either DNA or RNA)may be attached so as to bring about the replication of the attachedsequence or element.

An “expression vector” or “expression operon” refers to a nucleic acidsegment that may possess transcriptional and translational controlsequences, such as promoters, enhancers, translational start signals(e.g., ATG or AUG codons), polyadenylation signals, terminators, and thelike, and which facilitate the expression of a polypeptide codingsequence in a host cell or organism.

The terms “transform”, “transfect”, or “transduce”, shall refer to anymethod or means by which a nucleic acid is introduced into a cell orhost organism and may be used interchangeably to convey the samemeaning. Such methods include, but are not limited to, transfection,electroporation, microinjection, PEG-fusion and the like.

The introduced nucleic acid may or may not be integrated (covalentlylinked) into nucleic acid of the recipient cell or organism. Inbacterial, yeast, plant and mammalian cells, for example, the introducednucleic acid may be maintained as an episomal element or independentreplicon such as a plasmid. Alternatively, the introduced nucleic acidmay become integrated into the nucleic acid of the recipient cell ororganism and be stably maintained in that cell or organism and furtherpassed on or inherited to progeny cells or organisms of the recipientcell or organism. In other applications, the introduced nucleic acid mayexist in the recipient cell or host organism only transiently.

The phrase “consisting essentially of” when referring to a particularnucleotide or amino acid means a sequence having the properties of agiven SEQ ID NO:. For example, when used in reference to an amino acidsequence, the phrase includes the sequence per se and molecularmodifications that would not affect the basic and novel characteristicsof the sequence.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art.

The Compounds

The present invention provides amino, amido, and heterocyclic compoundscapable of modulating the receptor for advanced glycation end products(RAGE) activity.

Specifically, the invention provides amino, amido, and heterocycliccompounds capable of modulating the interaction of RAGE and its ligands,and uses of such compounds to treat diseases or conditions related toRAGE activity.

More specifically, the invention provides amino, amido, and heterocycliccompounds capable of modulating the interaction of RAGE and its ligandsbinding to the intracellular domain of the RAGE, and uses of suchcompounds to treat diseases or conditions related to RAGE activity.

In one aspect, the present invention provides a method for preventing,treating or ameliorating in a mammal a disease or condition that iscausally related to RAGE activity in vivo, which comprises administeringto the mammal an effective disease-treating or condition-treating amountof a compound according to formula A-Ia or A-Ib:

-   -   wherein        -   L¹ is —NH—, —CH₂—NH—, —CH₂—CH₂—NH—, —CO—NH— or            —CO—NH-L²-CO—NH—; and    -   Cy is substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl; or        -   L¹ is a bond and Cy is

-   -   -   R¹ is H, substituted or unsubstituted C₁-C₆ alkyl,            substituted or unsubstituted C₁-C₆ alkoxy, or halo;        -   each R² is independently selected from OH, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted acyl, substituted or            unsubstituted acylamino, substituted or unsubstituted            alkylamino, substituted or unsubstituted alkythio,            substituted or unsubstituted alkoxycarbonyl, substituted or            unsubstituted alkylarylamino, substituted or unsubstituted            amino, substituted or unsubstituted arylalkyl, sulfo,            substituted sulfo, substituted sulfonyl, substituted            sulfinyl, substituted sulfanyl, substituted or unsubstituted            aminosulfonyl, substituted or unsubstituted alkylsulfonyl,            substituted or unsubstituted arylsulfonyl, azido,            substituted or unsubstituted carbamoyl, carboxyl, cyano,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            cycloalkyl, substituted or unsubstituted heterocycloalkyl,            substituted or unsubstituted dialkylamino, halo, nitro, and            thiol; or two adjacent R¹ and R² groups may join together to            form a substituted or unsubstituted carbocyclic or            heterocyclic ring;        -   R³ is H, or substituted or unsubstituted C₁-C₆ alkyl;        -   the subscript n is 0, 1, 2, or 3;        -   L² is C₁-C₃ alkylene;        -   X is CH or N; Y is O or NR⁵;        -   R⁴ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted aryl,            or substituted or unsubstituted heteroaryl;        -   R⁵ is H or substituted or unsubstituted alkyl; and *            represents an attachment point;

    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   and stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, the conditions associated with RAGE activity include,without limitation, impaired wound healing, peripheral vascular disease,associated complications, obesity, Alzheimer's disease, cancers,arthritis, nephropathy, acute and chronic inflammation, retinopathy,atherosclerosis, erectile dysfunction, tumor invasion and metastasis,neuropathy, cardio- and cerebrovascular ischemia/reperfusion injury,sepsis, pneumonia, infection, liver injury, Amyotrophic lateralsclerosis, neuropathy, allergy, asthma, organ damage from pollutants,amyloidoses, and others.

In one embodiment, with respect to the compound of formula A-Ia or A-Ib,L¹ is —NH—. In another embodiment, L¹ is —CH₂—NH—. In anotherembodiment, L¹ is —CH₂—CH₂—NH—. In another embodiment, L¹ is —CO—NH—. Inanother embodiment, L¹ is —CO—NH-L²-CO—NH—; and L² is methylene,ethylene, or propylene. In one particular embodiment, L¹ is —CH₂—.

In another embodiment, with respect to the compound of formula A-Ia orA-Ib, L¹ is a bond and Cy is

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-II, A-III, A-IV, A-V, A-VI, A-VII:

wherein Cy, X, Y, R¹, R², R⁴, and n are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ib, thecompound is according to formula A-V:

wherein Cy, X, Y, R¹, R², R³, and n are as described for formula A-Ib.

In one embodiment, with respect to the compound of formula A-Ia-A-V, nis 1, 2 or 3. In another embodiment, n is 1 or 2. In yet anotherembodiment, n is 2. In a further embodiment, n is 0.

In one embodiment, with respect to the compound of formula A-Ia-A-V,each R² is independently selected from halo, amino, substituted amino,substituted or unsubstituted C₁-C₆ alkyl, CN, OH, methylthio, andsubstituted or unsubstituted C₁-C₆ alkoxy.

In another embodiment, with respect to the compound of formula A-Ia-A-V,each R² is independently selected from halo, substituted orunsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl, Br, —SMe, and substitutedor unsubstituted C₁-C₆ alkoxy.

In a particular embodiment, with respect to the compound of formulaA-Ia-A-V, n is 1 or 2; and each R² is independently Cl, Br, F, Me, Et,i-Pr, OMe, CF₃, CN, —SMe, —NHAc, or OH. In another particularembodiment, n is 1; and R² is —SMe. In another particular embodiment, nis 1; and R² is Br. In another particular embodiment, n is 1; and R² is—OH. In yet another particular embodiment, n is 2; and one of the R² isCl or F; and another R² is substituted or unsubstituted amino. In a moreparticular embodiment, n is 2; and one of the R² is Cl, and another R²is —NHAc or —NH—C(O)Me.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-VIIIa, A-VIIIb, A-VIIIc, or A-VIIId:

wherein Cy, and R¹ are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to A-IX:

wherein Cy, and R¹ are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ib, thecompound is according to formula A-Xa or A-Xb:

wherein Cy, and R¹ are as described for formula A-Ib.

In one embodiment, with respect to the compound of formula A-Ia-A-Xb, R¹is independently selected from H, halo, amino, substituted amino,substituted or unsubstituted C₁-C₆ alkyl, CN, OH, and substituted orunsubstituted C₁-C₆ alkoxy. In another embodiment, R¹ is independentlyselected from H, Cl, F, Me, Et, i-Pr, OMe, CF₃, CN or OH. In aparticular embodiment, R¹ is independently selected from H, F, and OMe.In another particular embodiment, R¹ is F. In a more particularembodiment, R¹ is OMe.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XIa, A-XIb, A-XIc or A-XId:

wherein Cy is as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to A-XII:

wherein Cy is as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ib, thecompound is according to formula A-XIIIa or A-XIIIb:

wherein Cy, and R¹ are described for formula A-Ib.

In one embodiment, with respect to the compound of formula A-Ib-A-XIIIb,Cy is substituted or unsubstituted aryl. In another embodiment, Cy issubstituted or unsubstituted phenyl. In another embodiment, Cy is phenylsubstituted with one or more groups selected from halo, substituted orunsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl, —SMe, carboxy, carbalkoxy,and substituted or unsubstituted C₁-C₆ alkoxy. In another embodiment, Cyis phenyl substituted with one or more groups selected from Cl, F, Me,Et, i-Pr, OMe, CF₃, CN, —SMe, —NHAc, —COOMe, and OH. In anotherembodiment, Cy is substituted or unsubstituted heteroaryl. In anotherembodiment, Cy is substituted or unsubstituted pyridyl. In anotherembodiment, Cy is pyridyl substituted with one or more groups selectedfrom halo, substituted or unsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl,—SMe, and substituted or unsubstituted C₁-C₆ alkoxy. In anotherembodiment, Cy is pyridyl substituted with one or more groups selectedfrom Cl, F, Me, Et, i-Pr, OMe, CF₃, CN, —SMe, —NHAc, and OH. In anotherembodiment, Cy is substituted or unsubstituted pyrrolyl, imidazolyl,triazolyl, thienyl, furanyl, thiazolyl, or oxazolyl. In a particularembodiment, Cy is substituted or unsubstituted thiazolyl. In aparticular embodiment, Cy is unsubstituted thiazolyl.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XIVa, A-XIVb, A-XIVc, or A-XIVd:

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to A-XV:

In one embodiment, with respect to the compound of formula A-Ib, thecompound is according to formula A-XVIa or A-XVIb:

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XVII:

wherein X, Y, R¹, and R⁴ are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ia-A-XVII(when present) X is CH. In another embodiment, X is N.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XVIIIa or A-XVIIIb:

wherein R¹, and R⁴ are as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ia-A-XVIIIb(when present) R¹ is independently selected from halo, amino,substituted amino, substituted or unsubstituted C₁-C₆ alkyl, CN, OH, andsubstituted or unsubstituted C₁-C₆ alkoxy. In another embodiment, R¹ isindependently selected from Cl, F, Me, Et, i-Pr, OMe, CF₃, CN or OH. Ina particular embodiment, R¹ is OMe. In one embodiment, Y is NH, or N-Me.In a particular embodiment, Y is O.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XIXa or A-XIXb:

wherein R⁴ is as described for formula A-Ia.

In one embodiment, with respect to the compound of formula A-Ia-A-XIXb(when present) R⁴ is substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In another embodiment, R⁴ isMe, i-Pr, cyclopropyl, CHF₂, CF₃, Ph, or pyridyl. In a particularembodiment, R⁴ is CHF₂, or CF₃. In a more particular embodiment, R⁴ isCF₃.

In one embodiment, with respect to the compound of formula A-Ia, thecompound is according to formula A-XXa or A-XXb:

In one embodiment, with respect to the compound of formula A-Ia or A-Ib,the compound is according to formula A-XIVa, A-XIVb, A-XIVc, A-XIVd,A-XV, A-XVIb, or A-XXb.

In another embodiment, with respect to the compound of formula A-Ia, thecompound is any one of the compounds listed in Table 2.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-I′:

-   -   wherein    -   each A¹, A², A³, and A⁴ is independently CR⁴ or N; provided that        only 1 or 2 of A¹, A², A³, and A⁴ are N at any one time;    -   Z is substituted amino, substituted hydroxyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   X is CR^(5a) or N;    -   R¹ is hydroxy, substituted hydroxyl, amino, or substituted        amino;    -   R² is H, alkyl or aryl;    -   R^(3a) is H, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl,        halo, or cyano;    -   each R⁴ is independently selected from H, OH, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted acyl, substituted or unsubstituted        acylamino, substituted or unsubstituted alkylamino, substituted        or unsubstituted alkythio, substituted or unsubstituted        alkoxycarbonyl, substituted or unsubstituted alkylarylamino,        substituted or unsubstituted amino, substituted or unsubstituted        arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,        substituted sulfinyl, substituted sulfanyl, substituted or        unsubstituted aminosulfonyl, substituted or unsubstituted        alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted cycloalkyl, substituted        or unsubstituted heterocycloalkyl, substituted or unsubstituted        dialkylamino, halo, nitro, and thiol;    -   R^(5a) is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, halo, or cyano; or R^(5a) and R^(3a) may        join together to form a substituted or unsubstituted carbocyclic        or heterocyclic ring; and each of the subscript m and n is        independently 1, 2, or 3;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compounds of formula B-I′, Z is

-   -   wherein B¹, B², B³, and B⁴ is independently CR⁴ or N; Y is        CR^(5b) or NR^(5a); R^(3b) is R^(3a); R^(3a) and R⁴ are as        described above; and R^(5b) is independently H, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, halo, or cyano;    -   or R^(5b) and R^(3b) may join together to form a substituted or        unsubstituted carbocyclic or heterocyclic ring

In one embodiment, the compound is according to formula B-I′; and eachof A¹, A², A³, and A⁴ is CR⁴.

In another embodiment, the compound is according to formula B-I′; andone of A¹, A², A³, and A⁴ is N, and the rest are independently CR⁴. Inone embodiment, each of R⁴ is H.

In another embodiment, each R⁴ is independently selected from H, halo,amino, substituted amino, substituted or unsubstituted C₁-C₆ alkyl, CN,OH, methylthio, and substituted or unsubstituted C₁-C₆ alkoxy. Inanother embodiment, each R⁴ is independently selected from H, halo,substituted or unsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl, Br, —SMe,and substituted or unsubstituted C₁-C₆ alkoxy. In another embodiment,each R⁴ is independently H, Cl, Br, F, Me, Et, i-Pr, OMe, CF₃, CN, —SMe,—NHAc, or OH.

In one embodiment, with respect to the compounds of formula B-I′, Z issubstituted amino. In another embodiment, Z is alkylamino, dialkylamino,phenylamino, diphenylamino, N-alkyl-N-benzylamino,N-alkyl-N-naphthylamino, or N-alkyl-N-phenylamino. In anotherembodiment, Z is diphenylamino, N-methyl-N-benzylamino,N-ethyl-N-naphthylamino, or N-methyl-N-phenylamino. In anotherembodiment, Z is substituted hydroxyl. In another embodiment, Z issubstituted or unsubstituted phenoxy. In another embodiment, Z isphenoxy or naphthyloxy substituted with alkyl, halo, carboxy,carbalkoxy, or CN. In another embodiment, Z is unsubstituted phenoxy,4-cyanophenoxy, 2-methylphenoxy, benzyloxy, naphthyloxy, or2-carboxyphenyloxy. In another embodiment, Z is

and wherein B¹, B², B³, B⁴, and R^(3b) are as described herein.

In one embodiment, the compound is according to formula B-I′; Z is asdescribed above; and each of B¹, B², B³, and B⁴ is CR⁴. In anotherembodiment, one of B¹, B², B³, and B⁴ is N, and the rest areindependently CR⁴. In another embodiment, the compound is according toformula B-I; and two of B¹, B², B³, and B⁴ is N, and the rest areindependently CR⁴. In one embodiment, each of R⁴ is H. In anotherembodiment, each R⁴ is independently selected from H, halo, amino,substituted amino, substituted or unsubstituted C₁-C₆ alkyl, CN, OH,methylthio, and substituted or unsubstituted C₁-C₆ alkoxy. In anotherembodiment, each R⁴ is independently selected from H, halo, substitutedor unsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl, Br, —SMe, andsubstituted or unsubstituted C₁-C₆ alkoxy. In another embodiment, eachR⁴ is independently H, Cl, Br, F, Me, Et, i-Pr, OMe, CF₃, CN, —SMe,—NHAc, or OH.

In another embodiment, the compound is according to formula B-I′; and Zis

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-I:

-   -   wherein    -   each A¹, A², A³, A⁴, B¹, B², B³, and B⁴, is independently CR⁴ or        N; provided that only 1 or 2 of A¹, A², A³, and A⁴ are N, and        only 1 or 2 of B¹, B², B³, and B⁴ are N at any one time;    -   X is CR^(5a) or N; X is CR^(5b) or N;    -   R¹ is hydroxy, substituted hydroxyl, amino, or substituted        amino;    -   R² is H, alkyl or aryl;    -   each R^(3a) and R^(3b) is independently H, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, halo, or cyano;    -   each R⁴ is independently selected from H, OH, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted acyl, substituted or unsubstituted        acylamino, substituted or unsubstituted alkylamino, substituted        or unsubstituted alkythio, substituted or unsubstituted        alkoxycarbonyl, substituted or unsubstituted alkylarylamino,        substituted or unsubstituted amino, substituted or unsubstituted        arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,        substituted sulfinyl, substituted sulfanyl, substituted or        unsubstituted aminosulfonyl, substituted or unsubstituted        alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted cycloalkyl, substituted        or unsubstituted heterocycloalkyl, substituted or unsubstituted        dialkylamino, halo, nitro, and thiol;    -   R^(5a) is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, halo, or cyano; or R^(5a) and R^(3a) may        join together to form a substituted or unsubstituted carbocyclic        or heterocyclic ring;    -   R^(5b) is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, halo, or cyano; or R^(5b) and R^(3b) may        join together to form a substituted or unsubstituted carbocyclic        or heterocyclic ring; and each of the subscript m and n is        independently 1, 2, or 3;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-II:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-III:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-IV:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-V:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another aspect, the present invention provides a method forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to RAGE activity in vivo, which comprisesadministering to the mammal an effective disease-treating orcondition-treating amount of a compound according to formula B-VI:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, the compound is according to formula B-I; and each ofA¹, A², A³, and A⁴ is CR⁴.

In another embodiment, the compound is according to formula B-I; and oneof A¹, A², A³, and A⁴ is N, and the rest are independently CR⁴.

In another embodiment, the compound is according to formula B-I; and twoof A¹, A², A³, and A⁴ is N, and the rest are independently CR⁴. In oneembodiment, the compound is according to formula B-I; and each of B¹,B², B³, and B⁴ is CR⁴. In another embodiment, the compound is accordingto formula B-I; and one of B¹, B², B³, and B⁴ is N, and the rest areindependently CR⁴. In another embodiment, the compound is according toformula B-I; and two of B¹, B², B³, and B⁴ is N, and the rest areindependently CR⁴. In one embodiment, each of R⁴ is H. In anotherembodiment, each R⁴ is independently selected from H, halo, amino,substituted amino, substituted or unsubstituted C₁-C₆ alkyl, CN, OH,methylthio, and substituted or unsubstituted C₁-C₆ alkoxy. In anotherembodiment, each R⁴ is independently selected from H, halo, substitutedor unsubstituted C₁-C₆ alkyl, CN, OH, —NHAc, Cl, Br, —SMe, andsubstituted or unsubstituted C₁-C₆ alkoxy. In another embodiment, eachR⁴ is independently H, Cl, Br, F, Me, Et, i-Pr, OMe, CF₃, CN, —SMe,—NHAc, or OH.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-VII:

-   -   and wherein X, Y, R¹, R², R^(3a), R^(3b), m, and n are as        described for formula B-I;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compound of formula B-I′, B-I, orB-VII, X is CR^(5a). In another embodiment, X is N. In one embodiment, Yis CR^(5b). In another embodiment, Y is N. In another embodiment, eachof X and Y is N.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-VIIIa, B-VIIIb, B-VIIIc, or B-VIIId:

-   -   and wherein R¹, R², R^(3a), R^(3b), R^(5a), R^(5b), m, and n are        as described for formula B-I;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compound of formula B-I′, B-I,B-VII, or B-VIIIa-B-VIIIc, R^(5a) is H, substituted or unsubstitutedalkyl, halo, or cyano. In another embodiment, R^(5a) and R^(3a) arejoined together to form a substituted or unsubstituted carbocyclic orheterocyclic ring. In another embodiment, R^(5b) is H, substituted orunsubstituted alkyl, halo, or cyano. In another embodiment, R^(5b) andR^(3b) are joined together to form a substituted or unsubstitutedcarbocyclic or heterocyclic ring.

In another embodiment, with respect to the compound of formula B-I′,B-I, B-VII, or B-VIIIa-B-VIIIc, R^(3a) is independently H, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, halo, or cyano. In anotherembodiment, R^(3a) is H. In another embodiment, R^(3a) is substituted orunsubstituted alkyl. In another embodiment, R^(3a) is Me, Et, i-Pr, CF₃,or CHF₂.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-IXa, B-IXb, or B-IXc:

-   -   and wherein R¹, R², R^(3b), m, and n are as described for        formula B-I;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, with respect to the compound of formula B-I′, B-I,B-VII, or B-VIIIa-B-IXc, R¹ is hydroxy or substituted hydroxy, Inanother embodiment, R¹ is OH, alkoxy, or acyloxy. In another embodiment,R¹ is OH. In another embodiment, R² is substituted or unsubstitutedalkyl. In another embodiment, R² is Me, Et, n-Pr, or i-Pr. In anotherembodiment, R² is substituted or unsubstituted aryl. In anotherembodiment, R² is Ph. In another embodiment, R² is H. In one embodiment,m is 1. In another embodiment, n is 1.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-Xa, B-Xb, B-Xc, or B-Xd:

-   -   and wherein R^(3b) is as described for formula B-I;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to the compound of formula B-I′,B-I, B-VII, or B-VIIIa-B-Xd, R^(3b) is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, halo, or cyano. In anotherembodiment, R^(3b) is H. In another embodiment, R^(3b) is substituted orunsubstituted alkyl. In another embodiment, R^(3b) is Me, Et, i-Pr, CF₃,or CHF₂.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XIa, B-XIb, B-XIc, B-XId, B-XIe,B-XIf, B-XIg, or B-XIh:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XIIa, B-XIIb, XIIc, B-XIId, B-XIIe,or B-XIIf:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XIIIa, B-XIIIb, B-XIIIc, or B-XIIId:

-   -   and wherein R^(3b) is as described for formula B-I;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;        -   or stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XIVa, or B-XIVb:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        -   or stereoisomers, isotopic variants and tautomers thereof

In another embodiment, with respect to the compound of formula B-I, thecompound is according to formula B-XVa, B-XVb, B-XVc, or B-XVd:

-   -   or a pharmaceutically acceptable salt, solvate or prodrug        -   or stereoisomers, isotopic variants and tautomers thereof

In another embodiment, with respect to the method, the compound isaccording to formula B-I′.

In another embodiment, with respect to the method, the compound isaccording to formula B-I.

In another embodiment, with respect to the method, the compound isaccording to formula B-II.

In another embodiment, with respect to the method, the compound isaccording to formula B-III.

In another embodiment, with respect to the method, the compound isaccording to formula B-IV.

In another embodiment, with respect to the method, the compound isaccording to formula B-V.

In another embodiment, with respect to the method, the compound isaccording to formula B-XId.

In another embodiment, with respect to the method, the compound isaccording to formula B-XIIIa.

In another embodiment, with respect to the method, the compound is anyone of the compounds listed in Table 3.

In another embodiment, with respect to the method, the compound is anyone of the compounds listed in Table 4.

In a further aspect, this invention provides a method of treating amammal susceptible to or afflicted with a condition from among thoselisted herein, and particularly, such condition as may be associatedwith RAGE. Such conditions include, without limitation, the disease orcondition is selected diabetes and its complications, impaired woundhealing, peripheral vascular disease and associated complications,obesity, cancers, arthritis, nephropathy, acute and chronicinflammation, retinopathy, atherosclerosis, cardiovascular diseaseerectile dysfunction, tumor invasion and metastases, cardio- andcerebrovascular ischemia/reperfusion injury, heart attack, stroke,myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis,pneumonia, infection, liver injury, liver damage, neuropathy infection,allergy, asthma, organ damage from pollutants, amyloidoses asthma,pollution-associated tissue damage, skin disorders, colitis, skin aging,lupus, and others.

In a further aspect, the conditions include, Alzheimer's disease,neuropathy, Amyotrophic lateral sclerosis, neuropathy and others.

In one embodiment, with respect to the method of treatment, the diseaseor condition is a diabetes associated complication.

In one embodiment, with respect to the method of treatment, the diseaseor condition is atherosclerosis.

In one embodiment, with respect to the method of treatment, the diseaseor condition is arthritis.

In one embodiment, with respect to the method of treatment, the diseaseor condition is neurodegeneration.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds according to the formulae above. Prodrugsare derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

Pharmaceutical Compositions

When employed as pharmaceuticals, the compounds of this invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound-administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of this invention can be administered bya variety of routes including oral, rectal, intraocular, transdermal,subcutaneous, intravenous, intramuscular, intraperitoneal, interdermal,directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended route of delivery, the compounds of thisinvention are preferably formulated as either injectable or oralcompositions or as salves, as lotions or as patches all for transdermaladministration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, a compound as describedherein is usually a minor component (from about 0.1 to about 50% byweight or preferably from about 1 to about 40% by weight) with theremainder being various vehicles or carriers and processing aids helpfulfor forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as an ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

The compounds of this invention can also be administered by atransdermal device. Accordingly, transdermal administration can beaccomplished using a patch either of the reservoir or porous membranetype, or of a solid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of this invention can also be administered locally to theeye for the treatment of diabetic neuropathy. Suitable compositionsinclude those administrable by eye drops, injections or the like. In thecase of eye drops, the composition can also optionally include, forexample, ophthalmologically compatible agents such as isotonizingagents, buffering agents, surfactants, stabilization agents, and otheringredients. For injection, the compound can be provided in an injectiongrade saline solution, in the form of an injectable liposome solution,slow-release polymer system or the like.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions of this invention. The present invention,however, is not limited to the following pharmaceutical compositions.

Formulation 1—Tablets

A compound of the invention is admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into240-270 mg tablets (80-90 mg of active amide compound per tablet) in atablet press.

Formulation 2—Capsules

A compound of the invention is admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active amide compound per capsule).

Formulation 3—Liquid

A compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum(4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and thenmixed with a previously made solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate(10 mg), flavor, and color are diluted with water and added withstirring. Sufficient water is then added to produce a total volume of 5mL.

Formulation 4—Tablets

A compound of the invention is admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active amide compound) in a tabletpress.

Formulation 5—Injection

A compound of the invention is dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/ml.

Formulation 6—Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted atabout 75° C. and then a mixture of a compound of the invention (50 g)methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate(10 g), and propylene glycol (120 g) dissolved in water (about 370 g) isadded and the resulting mixture is stirred until it congeals.

Methods of Treatment

Types 1 and 2 diabetes are on the rise in the United States andworld-wide [1-3]. The long-term consequences of diabetes ensue from thedirect and indirect effects of hyperglycemia. Diabetes attacks themacro- and microvasculature and is well-established as a leading causeof heart attacks and stroke, blindness, renal failure, amputations, andperipheral neuropathies. The strong epidemiological links betweendiabetes and Alzheimer's disease raise the possibility that devastatingloss of quality and duration of life in the form of irreversible chronicdisease often accompany diabetes. Despite significant advances in thetreatment of hyperglycemia, definitive means to prevent thecomplications of diabetes are not yet on the immediate horizon. Indeed,rigorous control of hyperglycemia, particularly in older individuals,may be fraught with significant sequelae, such as striking hypoglycemia,seizures, cardiac ischemia and death [4-6].

The products of nonenzymatic glycation and oxidation of proteins andlipids, the advanced glycation endproducts (AGEs), form and accumulateto accelerated degrees in hyperglycemia [7]. AGEs may be detected in theplasma, urine, skin and other tissues of diabetic subjects and theirpresence has been linked to the development of complications ofdiabetes. AGEs impart their effects in part by non-receptor mediatedmechanisms, such as by cross-linking of the body's proteins,particularly those that are long-lived such as in basement membranes.AGEs also exert their effects by receptor-dependent mechanisms; thechief receptor for AGE is the receptor for AGE or RAGE. Extensiveevidence reveals that expression of RAGE, a member of the immunoglobulinsuperfamily of cell surface molecules, is increased in animal model andhuman diabetic tissues, such as in the macro- and microvascular tissues.RAGE is a multi-ligand receptor and the finding that RAGE binds at leastcertain members of the pro-inflammatory S100/calgranulin family and highmobility group box 1 (HMGB1) indicate that inflammatory mechanismscontribute integrally to the pathogenesis of complications. Indeed,non-AGE RAGE ligands also accumulate in human and animal model diabetictissues [8-9]. Once thought highly unlikely, the role of inflammation inat least certain forms/stages of diabetic complications is now widelyappreciated. Pharmacological and genetic approaches by multiplelaboratories, working independently, have provided very strong supportfor roles for RAGE in the pathogenesis of diabetic complications. Forexample, administration of antibodies to RAGE or soluble RAGE (thelatter the extracellular ligand binding domain of RAGE) or geneticdeletion of RAGE significantly reduces accelerated diabeticatherosclerosis in mice; ischemia/reperfusion injury in the diabetichearts; pathological and functional indices of nephropathy; pathologicaland functional indices of neuropathy; and improves wound healing indiabetic animals [8-9].

Accumulating evidence reveals that levels of soluble RAGEs (cell surfacecleaved RAGE and the endogenous secretory (splice variant)) may bebiomarkers of diabetes and its complications in human subjects; levelsof soluble RAGEs appear to be modulated by therapeutic interventions,thereby raising the significance of measuring these forms of circulatingRAGE.

In this direct context, the inventors and others demonstrated that thecytoplasmic domain of RAGE is essential for the impact of RAGEligand-RAGE interaction in modulation of gene expression and generationof vascular and inflammatory cell dysfunction. The cytoplasmic domain ofRAGE does not appear to exert its downstream signaling impact simply byendogenous phosphorylation; hence, the inventors sought to test thepremise that intracellular binding effectors were essential to bind tothe RAGE tail and thus facilitate engagement of intracellular signalingpathways. Toward that end, the inventors performed a yeast-two-hybridassay using the RAGE tail as “bait.” From this experimental work, theinventors discovered and published in 2008 that the cytoplasmic domainof RAGE interacts with the formin molecule, mDia1 (diaphanous 1) andthat mDia1 is required for the impact of RAGE signaling in multiple celltypes such as smooth muscle cells, macrophages, cardiomyocytes andendothelial cells [10-13].

Fundamental observations link mDia1 to the pathological indices of RAGEsignal transduction directly relevant to diabetic complications. Thus,modulating the interaction between RAGE and mDia1 is desirable fortreating diseases and conditions where RAGE is implicated.

Further to the above, it will be appreciated that the compoundsdescribed herein act as modulators of RAGE binding to its intracellularligands (e.g., mDia1) and thereby reduce or prevent the activation ofNF-κB regulated genes, such as the cytokines IL-1, and TNF-α, andminimize the generation of oxidative stress. The ability of thecompounds described herein to antagonize or inhibit the binding ofphysiological ligands to the intracellular tail of RAGE renders themwell suited to use as therapeutic agents for treating or managingdiseases or conditions related to RAGE activity. More particularly, theamino, amido, and heterocyclic compounds described herein may be used totreat, for example, diabetes complications, inflammation,neurodegeneration, obesity, cancer, ischemia/reperfusion injury,cardiovascular disease, Alzheimer's Disease, and other diseasesunderstood to be related to RAGE activity. Such compounds may be used toimpair downstream signaling events resulting from, for example, AGE-RAGEinteraction, which contributes to diabetic complications,S100/EN-RAGE/calgranulin-RAGE interaction, which contributes toinflammatory diseases, β-amyloid-RAGE interaction, which contributes toAlzheimer's Disease, and high mobility group box 1 (HMGB1)-RAGEinteraction, which contributes to, e.g., inflammation and cancer.

Diabetes and Diabetes Complications

Further to the above, the amino, amido, and heterocyclic compoundsdescribed herein are useful for managing and/or treating complicationsassociated with diabetes. Nonenzymatic glycoxidation of macromoleculesresults in the formation of advanced glycation endproducts (AGEs). Theterm AGEs refers to a heterogeneous group of compounds generated throughthe non-enzymatic glycation or glycoxidation of proteins, lipids, andnucleic acids. More particularly, AGEs are the result of a series ofcomplex biochemical reactions that involve the formation of Amadoriproducts, glyceraldehyde-3-phosphate, and the reactive carbonylmethylglyoxal (MG). See, for example, Manigrasso et al. (2014, Trends inEndocrin Metab 25:15-22); the entire content of which, includingreferences cited therein, is incorporated herein by reference.Nonenzymatic glycoxidation of macromolecules is known to be enhanced inthe presence of hyperglycemia and other conditions associated withsystemic or local oxidant stress. It is also known to be enhanced inrenal failure and at sites of inflammation, and amongst other localesassociated with neurodegeneration, obesity, and cancer. Schmidt et al.(1995, Nature Med. 1:1002-1004), for example, have shown that AGEsaccumulate generally in the vasculature and tissues of patients withdiabetes. Other research has demonstrated that AGEs also accumulate inthe vasculature focally, as observed in the joint amyloid composed ofAGE-β2-microglobulin found in patients with dialysis-related amyloidosis(Abedini et al. 2013, FEBS Lett 587:1119-1127; Miyata et al. 1993, J.Clin. Invest. 92:1243-1252; Miyata et al. 1996, J. Clin. Invest.98:1088-1094). AGE production is also directly accelerated byhyperglycemia. AGE formation is also frequently associated with anincrease in reactive oxygen species (ROS) (Fu et al. 1994, Diabetes43:676-683). Although AGEs accumulate slowly in both plasma and tissuesduring aging (Brownlee et al. 1988, N Engl J Med 318:1315-1321; Hallamet al. 2010, Aging Cell 9:776-784; Schleicher et al. 1997, J Clin Inv99:457-468), they are markedly increased in patients with diabetes(Makita et al. 1991, N Engl J Med 325:836-842).

Suitable animal models in which to study diabetes complications areknown in the art and are described in, for example, Manigrasso et al.(2014, Trends in Endocrin Metab 25:15-22); Stirban et al. (2014,Molecular Metabolism 3:94-108); Johnson et al. (2014, EJNMMI Res 4:26);Tekabe et al. (2014, Int J Mol Imaging Article Id 695391); Kaida et al.(2013, Diabetes 62:3241-3250); Tekabe et al. (2013, EJNMMi Res 3:37);Calcutt et al. (2009, Nat Rev Drug Discov 8:417-429); Dauch et al.(2013, J Neuroinflammation 10:64); Juranek et al. (2013, Diabetes62:931-943); Singh et al. (2014, Korean J Physiol Pharmacol 18:1-14);Ramasamy et al. (2012, Vascular Pharmacol 57: 160-167); Montagnani(2008, Br J Pharmacol 154:725-726); Nakamura et al. (1993, Am J Pathol143:1649-1656); Lin et al. (2003, Atherosclerosis 168:213-220); Hofmannet al. (2002, Diabetes 51:2082-2089); Lin et al. (2002, Atherosclerosis163:303-311); Vlassara et al. (1992, Proc Natl Acad Sci 89:12043-12047);Brownlee et al. (1986, Science 232:1629-1632); Li et al. (1996, ProcNatl Acad Sci 93:3902-3907); Park et al. (1998, Nature Med 4:1025-1031);Kislinger et al. (2001, Arteriosclerosis, Thrombosis, and VascularBiology 21:905-910); Bucciarelli et al. (2002, Circulation106:2827-2835); Wendt et al. (2006, Atherosclerosis 185:70-77); theentire content of each of which is incorporated herein by reference.

Diabetic Complications—Heart

More particularly, animal models of human diabetes involving diabeticcomplications of the heart include ex vivo isolated perfused heartischemia/reperfusion, left anterior descending coronary artery ligation,and cardiac autonomic neuropathy. References describing such models areknown in the art and described in, for example, Stables et al. (2014,Autonom Neurosci 177: 746-80), Bucciarelli et al. (2000, Circulation(Supplement) 102: #563, II-117), and Aleshin et al. (2008, Am J PhysiolHeart Circ Physiol 294: H1823-H1832); the entire content of each ofwhich is incorporated herein by reference.

Diabetic Complications—Kidney

More particularly, animal models of human diabetes involving diabeticcomplications of the kidney include OVE26 mice, streptozotocin inducedanimals, Db/db mice, and nephrectomy. References describing such modelsare known in the art and described in, for example, Kaur et al. (2014,Inflammopharmacology 22:279-293), Reiniger et al. (2010, Diabetes 59:2043-2054), and Wendt et al. (2003, American Journal of Pathology162:1123-1137); the entire content of each of which is incorporatedherein by reference.

Diabetic Complications—Retinopathy

More particularly, animal models of human diabetes involving diabeticcomplications leading to retinopathy include streptozotocin inducedanimals, Db/db mice, and Akita mice. References describing such modelsare known in the art and described in, for example, Lai et al. (2013, JDiabetes Res 013:106594) and Barile et al. (2005, Invest Ophthalmol VisSci 46:2916-2924); the entire content of each of which is incorporatedherein by reference.

Diabetic Complications—Neuropathy

More particularly, animal models of human diabetes involving diabeticcomplications leading to neuropathy include Swiss Webster mice, Db/dbmice, and Sciatic nerve transection/crush. References describing suchmodels are known in the art and described in, for example, Juranek etal. (2010, Biochem Insights 2010:47-59), Juranek et al. (2013, Diabetes62: 931-943), Islam (2013, J Diabetes Res 2013:149452); the entirecontent of each of which is incorporated herein by reference.

Animal models of diabetes in general include streptozotocin inducedanimals, Akita mice, Db/db mice, and Ob/ob mice. These animal models areknown in the art and described in, for example, Park et al. (1998,Nature Medicine 4:1025-1031), Wendt et al. (2006, Atherosclerosis185:70-77), Wang et al. (2014, Curr Diabetes Rev 10: 131-145), andAcharjee et al. (2013, Can J Diabetes 37: 269-276); the entire contentof each of which is incorporated herein by reference.

Immune/Inflammatory Responses

As described herein and demonstrated in, for example, FIG. 10, Example4, and Table 5, the compounds described herein are useful in treatinginflammation. In that inflammation is a common feature underlying all ofthe diseases and conditions described herein, the utility of thecompounds described herein in reducing inflammation in the animal modelof inflammation underscores the reasonable expectation that thesecompounds will also be efficacious in the context of, for example,diabetes complications, obesity, cancer, ischemia/reperfusion injury,cardiovascular disease, neurodegeneration, Alzheimer's Disease, cysticfibrosis, multiple sclerosis, rheumatoid arthritis, psoriasis, atopicdermatitis, and eczema.

As alluded to above, RAGE is a receptor for many members of theS100/calgranulins, a family of closely related calcium-bindingpolypeptides that accumulate at sites of chronic immune/inflammatoryresponses, such as those observed in cystic fibrosis and rheumatoidarthritis. RAGE, moreover, is known to mediate the proinflammatoryeffects of S100/calgranulins on a variety of cells, includinglymphocytes and mononuclear phagocytes. Indeed, RAGE-ligand interactionswith, e.g., proinflammatory S100/calgranulins, high mobility group box 1(HMGB1), and/or AGEs are implicated as having a pivotal role in theinflammatory cascade in general. See, for example, Ramasamy et al.(2012, Vascular Pharmacol 57: 160-167); Andersson et al. (2011, Annu RevImmunol 29:139-162); the entire content of each of which, includingreferences cited therein, is incorporated herein by reference. Studiesusing in vitro models and in animal models of the delayed-typehypersensitivity (DTH) response, colitis in IL-10 null mice,collagen-induced arthritis, and experimental autoimmune encephalitismodels further underscore the fundamental role of RAGE-ligandinteractions in various inflammatory diseases including rheumatoidarthritis and multiple sclerosis.

RAGE is also been implicated in inflammatory diseases of the skin suchas but not limited to psoriasis, atopic dermatitis, and eczema.Psoriasis may, moreover, be accompanied by arthropathic symptoms thatare similar to those seen in rheumatoid arthritis. High levels ofpro-inflammatory cytokines, particularly IL-1 and IL-8, are detected inpsoriatic lesions. IL-8 is a chemotactic factor for neutrophils, whichare known to synthesize and secrete S100 proteins. As indicated hereinabove, S100 proteins are RAGE ligands, which interaction leads to thepropagation of immune and inflammatory responses that contribute andlead to a variety of diseases/conditions described herein. Psoriasin(S100A7), a member of the S100 gene family, is a secreted proteinisolated from psoriatic skin. Linkage of psoriasis geneticsusceptibility to distinct overexpression of S100 proteins in the skinhas, furthermore, been demonstrated (Semprini et. al. 2002, Hum. Genet.111:310-3). The compounds described herein are therefore envisioned astherapeutic agents for psoriasis in light of their ability to inhibitRAGE mediated downstream signaling.

High Mobility Group Box 1 (HMGB1)

HMGB1, which is also known as amphoterin, has dual activities. It wasoriginally characterized as a structural protein localized to thenucleus where it functions to stabilize DNA structure and modulatetranscriptional activity (Stros et al. 2010, Biochem Biophys Acta1799:101-113). HMGB1 was also later discovered to be an activelysecreted cytokine, produced by macrophages and other inflammatory cellsduring the innate immune response to invasion (Wang et al. 1999, Science285:248-251). Like other members of the proinflammatory cytokine family,biologically active HMGB1 can be expressed on the plasma membrane orreleased by activated inflammatory cells to accumulate in vivo duringinfection and injury. HMGB1 acts as an effector molecule capable ofaltering the metabolic and immunological activities of hematopoietic,epithelial, and neuronal cells. The breadth of its effector functions isreflected in its known activities, which include significant roles infever, anorexia, acute-phase responses, and vascular leakage syndrome.HMGB1 acts in synergy with other cytokines and pathogen-derivedmolecules in these diseases/conditions. The contribution of HMGB1 tothese and other pathological conditions is underscored by the numerousdemonstrations that administration of agents that specifically inhibitHMGB1 activity (antibodies, antagonist proteins, release inhibitors) toanimals with ischemia and inflammatory diseases interrupts theprogression of tissue injury and suppresses inflammatory responses intreated animals. See, Andersson et al. (2011, Annu Rev Immunol29:139-162) for a review.

The available evidence thus demonstrates that HMGB1 is a generalmediator of inflammation, implicated in a plethora of inflammatory andautoimmune diseases. In that HMGB1 is a ligand for RAGE, these findingsunderscore the role of RAGE as a general mediator of inflammation andrender apparent that targeting RAGE activity with the intent to inhibitdownstream signaling therefrom has significant promise and use of thecompounds described herein for the treatment of subjects afflicted withdiseases/conditions characterized by inflammation and/or autoimmunitywould attenuate clinical signs and symptoms of inflammation in suchsubjects.

Animal models of autoimmunity/inflammation include those involvingdelayed type hypersensitivity, Rheumatoid arthritis, Systemic lupuserythematosis, Ulcerative colitis, Crohn's disease, Psoriasis, Behcet'ssyndrome, Type 1 diabetes, Vasculitis, Glomerulonephritis, Sarcoidosis.Such animal models are known in the art and described in, for example,Hofmann et al. (1999, Cell 97:889-901), Hofmann et al. (2002, Genes andImmunity 3:123-135), Webb et al. (2014, Biochem Pharmacol 87:121-130),Sakata et al. (2012, Exp Diabetes Res 2012:256707), Goyal et al. (2014,Inflammopharmacology 22:219-233), Lu et al. (2014, Life Sci 108(1):1-6),Starr et al. (2014, Aging Dis 5: 126-136); the entire content of each ofwhich is incorporated herein by reference.

Obesity

Animal models of human obesity are known in the art and involve feedingmice a 45% high fat diet or a 60% high fat diet. Such models aredescribed in, for example, Song et al. (2014, Diabetes 63(6): 1948-1965)and Aydin et al. (2014, Nutrition 30: 1-9); the entire content of eachof which is incorporated herein by reference.

Cancer

Abnormal expression of RAGE and its ligands has been reported in anumber of cancers, including prostatic, colorectal, pancreatic, lung,and oral squamous cell cancers. It is, moreover, thought that theinteraction of RAGE with its ligands contributes to cancer invasion andmetastasis. The interaction between RAGE and HMGB1 triggers theactivation of key cell signaling pathways, such as NF-κB, p38, p44/42MAPKs, and activation of these pathways contributes to cancerprogression and metastasis (Sims et al. 2010, Annu Rev Immunol28:367-388; Sparvero et al. 2009, J Transl Med 7:17; Lodgson et al.2007, Curr Mol Med 7:777-789; Kuniyasu et al. 2003, Oncol Rep10:445-448; Kuniyasu et al. 2003, Int J Cancer 104:722-727; Sasahira etal. 2005, Virchows Arch 446:411-415; Kuniyasu et al. 2005, Am J Pathol166:751-760; Kuniyasu et al. 2004, Pathobiology 71:129-136; Sasahira etal. 2007, Virchows Arch 450:287-295; Kuniyasu et al. 2002, J Pathol196:163-170; the entire content of each of which is incorporated hereinby reference). Further to the above, Rai et al. (2012, J Exp Med209:2339-2350) and Arumugam et al. (2012, Clin Canc Res 18:4356-4364),for example, describe animal model systems in which the contribution ofRAGE to various cancers has been investigated and validated.

Further to the above, RAGE and its ligand HMGB1 are believed to play animportant role in prostate cancer. Indeed, Zhao et al. (2014, Am JCancer Res 4:369-377) addressed the significance of these effectormolecules in a retrospective study designed to investigate theexpression of RAGE and HMGB1 and their clinical impact on prostatecancer progression and prognosis. The expression of RAGE and HMGB1 wasassessed by immunohistochemistry in cancer lesions from 85 confirmedprostate cancer cases. Zhao et al. demonstrated that there is a strongcorrelation between RAGE and HMGB1 expression (P<0.001) and theexpression of RAGE, HMGB1 and their co-expression were all associatedwith advanced tumor clinical stage (P<0.05 for all). RAGE expression wasalso associated with the prostate specific antigen (PSA) level(P=0.014). Co-expression of RAGE and HMGB1 was also associated with pooroverall survival in patients with stage III and IV prostate cancer(P=0.047). These results suggest that the expression of RAGE and HMGB1is associated with progression and poor prognosis of prostate cancer.RAGE and HMGB1 are, therefore, proposed to be molecular targets fornovel forms of therapy for prostate cancer.

Tumors/Tumorigenesis

Animal models for various forms of human cancers are known in the artand include those recapitulating aspects of human lung cancer, melanoma,colon cancer, pancreatic cancer, and breast cancer and bio-models ofcancer for in silico screening. Such animal models are known in the artand are described in, for example, Taguchi et al. (2000, Nature405:354-360), Arumugam et al. (2004, Journal of Biological Chemistry279:5059-5065), Huang et al. (2006, Surgery 139:782-788), Huang et al.(2006, Surgery 139:782-788), Fuentes et al. (2007, Dis Colon Rectum50:1230-1240), Arumugam et al. (2012, Clin Cancer Res 18: 4356-4364), Yuet al. (2014, J Gastric Cancer 14:67-86), Fleet (2014, Am J PhysiolGastrointest Liver Physiol. 307(3):G249-59), Lindner (2014, Semin Oncol41: 146-155), Wang et al. (2014, Biofabrication 6(2):022001), Budhu etal. (2014, Curr Opin Genet Dev 24: 46-51, 2014); the entire content ofeach of which is incorporated herein by reference.

Ischemia/Reperfusion Injury

In, for example, animal models of hind limb ischemia in mice with orwithout diabetes, suppressing RAGE ligands has led to improvement ofangiogenic response to limb ischemia. See, for example, Tamarat et al.(2003, Proc Natl Acad Sci 100:14); Goova et al. (2001, Am J Pathol159:513-525); Tekabe et al. (2010, J Nuc Med 51:92-97); Tekabe et al.(2013, EJNMMi Res 3:37); Bucciarelli et al. (2008, Diabetes57:1941-1951); Shang et al. (2010, PLoS 5:e10092); Ma et al. (2009, JCell Mol Med 13:1751-1764); the entire content of each of which isincorporated herein by reference.

Erectile Dysfunction

Relaxation of the smooth muscle cells in the cavernosal arterioles andsinuses results in increased blood flow into the penis, raising corpuscavernosum pressure to culminate in penile erection. Nitric oxide isconsidered the principle stimulator of cavernosal smooth musclerelaxation (See Wingard et al. (2001, Nature Medicine 7:119-122). Inthat RAGE activation produces oxidants via an NADH oxidase-like enzyme(Yan et al. 1994, J. Biol. Chem. 269:9889-9887), it is thought tosuppress nitric oxide circulation. Inhibiting activation of RAGEsignaling pathways is, therefore, predicted to attenuate oxidantgeneration. Inhibition of RAGE-mediated activation of Rho-kinases isalso predicted to enhance and stimulate penile erection independently ofnitric oxide. Accordingly, compounds such as those described herein thatact to inhibit downstream RAGE signaling may be used to advantage topromote and facilitate penile erection.

Respiratory Diseases

Patients with chronic obstructive pulmonary disease exhibit increasedRAGE expression in the lung and elevated soluble RAGE levels in thebronchial alveolar fluid (Yan et al. 2003, Nature Med 9:287-293; Miniatiet al. 2011, Respir Res 12:37). Increased RAGE receptor and ligandlevels have also been detected in asthmatic patients (Watanabe et al.2010, Respir Med 105:519-525), indicating an active role for RAGE inlung inflammation. See also Wu et al. (2013, Mol Cell Biochem380:249-257); Sukkar et al. (2012, Br J Pharmacol 167:1161-1176).

Furthermore, in severe exacerbations of asthma there is an intense,mechanistically heterogeneous inflammatory response involving neutrophiland eosinophil accumulation and activation. Neutrophils are, moreover, asignificant source of S100 proteins, key ligands for RAGE implicated inthe propogation of the immune response and inflammation as describedherein above. Accordingly, inhibitors of RAGE downstream signaling wouldbe expected to be efficacious in the treatment of asthma. In that thepropagation step in the immune response in the lung driven by S100-RAGEinteraction is thought to lead to the activation and/or recruitment ofinflammatory cells, such as neutrophils, which are significant sourcesof damaging proteases in chronic obstructive pulmonary diseases such asemphysema, the compounds described herein that act as RAGE inhibitorscan be used to treat chronic obstructive pulmonary diseases.

Animal models for assessing the therapeutic potential of compoundsdescribed herein are presented in, for example, Akirav et al. (2014,PLoS One 9:e95678); and Constant et al. (2002, J Clin Invest110:1441-1448); the entire content of each of which is incorporatedherein by reference.

Amyloidoses

Compounds described herein are also envisioned as useful for treatingamyloidoses and Alzheimer's Disease (AD). RAGE is known to bind β-sheetfibrillar material and deposition of amyloid has been shown to enhanceexpression of RAGE. The brains of AD patients exhibit increasedexpression of RAGE in neurons and glia (Yan et al. 1996, Nature382:685-691). Binding of Aβ-RAGE on microglia activates these cells, asreflected by increased motility and expression of cytokines, whereasbinding of Aβ-RAGE on neurons initially activates the cells, butultimately leads to cytotoxicity. Inhibition of RAGE-amyloid interactiondecreases expression of cellular RAGE and cell stress markers (as wellas NF-κB activation) and diminishes amyloid deposition (Yan et al. 2000,Nat. Med. 6:643-651). These findings suggest that a role forRAGE-amyloid interaction exists, both with respect to perturbation ofcellular properties in an environment enriched for amyloid at earlystages of disease and progressively during the course of disease asamyloid accumulates.

Neurodegeneration

Animal models of human neurodegenerative diseases are known and includemouse models of Alzheimer's Disease, humanized mouse models ofAmyotrophic lateral sclerosis, and mouse models of Huntington's disease.Such animal models are described in, for example, Millington et al.(2014, Biomed Res Inst 2014:309129), Yan et al. (1996, Nature382:685-691), Yan et al. (1997, Proc. Natl. Acad. Sci. 94:5296-5301),Bard et al. (2014, J Biomol Screen 19: 191-204), Neha et al. (2014, LifeSci 109(2):73-86), and Turner et al. (2013, Amyotroph Lateral SclerFrontotemporal Degener. 14 Suppl 1:19-32); the entire content of each ofwhich is incorporated herein by reference.

Atherosclerosis

Examples of animal models of human atherosclerotic disease includeapolipoprotein E null mice and Low Density Lipoprotein Receptor nullmice. See, for example, Kapourchali et al. (2014, World J Clin Cases 2:126-132), Harja et al. (2008, J. Clin. Invest. 1118: 183-194), Nagareddyet al. (2013, Cell Metab 17: 695-708); the entire content of each ofwhich is incorporated herein by reference.

In light of that which is understood in the art and described hereinregarding the prominent role of RAGE in diseases/conditionscharacterized by acute and chronic inflammation, methods are presentedherein for treating such diseases/conditions, including but not limitedto diabetic complications, ischemia, skin inflammation (e.g., psoriasisand atopic dermatitis), lung inflammation (e.g., asthma and chronicobstructive pulmonary disease), vascular permeability, nephropathy,atherosclerosis, retinopathy, Alzheimer's Disease, erectile dysfunction,and tumor invasion and/or metastasis, which methods compriseadministering to a subject in need thereof a compound described hereinin a therapeutically effective amount. In a particular embodiment, atleast one compound described herein is utilized, either alone or incombination with one or more known therapeutic agents. In a furtherparticular embodiment, the present invention provides a method fortreating RAGE mediated human diseases, wherein treatment alleviates oneor more symptoms resulting from that disorder, the method comprisingadministration to a human in need thereof a therapeutically effectiveamount of a compound described herein.

In vitro assays relating to RAGE-mediated diseases and animal modelsystems thereof are described in US2012/0088778, US2010/0254983,US2010/0119512, U.S. Pat. No. 7,361,678, WO2007/089616, andUS2010/0249038, the entire content of each of which is incorporatedherein by reference.

Further to the above, the present compounds are modulators ofinteraction between RAGE and RAGE ligands and are used as therapeuticagents for the treatment of conditions in mammals that are causallyrelated or attributable to RAGE activity. Accordingly, the compounds andpharmaceutical compositions of this invention find use as therapeuticsfor preventing and/or treating a variety of conditions related to, forexample, diabetes complications in mammals, including humans.

In a method of treatment aspect, this invention provides a method oftreating a mammal susceptible to or afflicted with a conditionassociated with diabetes complications, Alzheimer's disease, cancers,arthritis, nephropathy, acute and chronic inflammation, retinopathy,atherosclerosis, erectile dysfunction, tumor invasion and metastasis,and others, which method comprises administering an effective amount ofone or more of the pharmaceutical compositions just described.

In additional method of treatment aspects, this invention providesmethods of treating a mammal susceptible to or afflicted with aninflammatory condition causally related or attributable to RAGEactivity. Such condition and disorders include, without limitation,diabetes and its complications, impaired wound healing, peripheralvascular disease and associated complications, obesity, Alzheimer'sdisease, cancers, arthritis, nephropathy, acute and chronicinflammation, retinopathy, atherosclerosis, cardiovascular disease,erectile dysfunction, tumor invasion and metastases, neuropathy, cardio-and cerebrovascular ischemia/reperfusion injury, heart attack, stroke,myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis,pneumonia, infection, liver injury, liver damage, Amyotrophic lateralsclerosis, neuropathy infection, allergy, asthma, organ damage frompollutants, amyloidoses asthma, pollution-associated tissue damage, skindisorders, colitis, skin aging, lupus, and others. Such methods compriseadministering an effective condition-treating or condition-preventingamount of one or more of the pharmaceutical compositions just described.

As a further aspect of the invention there is provided the presentcompounds for use as a pharmaceutical especially in the treatment orprevention of the aforementioned conditions and diseases. Also providedherein is the use of the present compounds in the manufacture of amedicament for the treatment or prevention of one of the aforementionedconditions and diseases. Also provided herein are the present compoundsfor use in treating or preventing one of the aforementioned conditionsand diseases, wherein at least one of the compounds described herein isadministered to a subject in need thereof in a therapeutically effectiveamount sufficient to antagonize/reduce RAGE activity and thereby treatthe condition or disease.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions, such as,e.g., arthritis, diabetes, or asthma, the regimen for treatment usuallystretches over many months or years, so oral dosing is preferred forpatient convenience and tolerance. With oral dosing, one to five andespecially two to four and typically three oral doses per day arerepresentative regimens. Using these dosing patterns, each dose providesfrom about 0.01 to about 20 mg/kg of the compound of the invention, withpreferred doses each providing from about 0.1 to about 10 mg/kg andespecially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses. Modes ofadministration suitable for mucosal sites are also envisioned herein andinclude without limitation: intra-anal swabs, enemas, intranasal sprays,and aerosolized or vaporized compounds and/or compositions for deliveryto the lung mucosa. One of skill in the art would choose an appropriatedelivery models based on a variety of parameters, including the organ ortissue site in a patient with a disease or condition that is mostseverely affected by the disease or condition.

When used to prevent the onset of an inflammatory condition orautoimmune disorder, the compounds of this invention will beadministered to a patient at risk for developing the condition ordisorder, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The compounds of this invention can be administered as the sole activeagent or they can be administered in combination with other agents,including other compounds that demonstrate the same or a similartherapeutic activity and are determined to safe and efficacious for suchcombined administration.

General Synthetic Procedures

The amino, amido, and heterocyclic compounds of this invention may bepurchased from various commercial sources or can be prepared fromreadily available starting materials using the following general methodsand procedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds of the invention may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis.

For example, exemplary compounds of formula B-I′ and B-I can be preparedfollowing the methods described in Schemes 1 and 2.

Assay Methods

Primary Screen (High-Throughput Screening Assay)

Primary screening was a two-step process in which compounds were firsttested in a high throughput assay at one concentration (10 uM).Compounds that reduced binding of RAGE tail (ctRAGE) by at least 50%were then selected and subjected to 4-point dose response (10 uM, 1 uM,0.1 uM and 0.01 uM) (FIGS. 1, 4, and 5). Compounds that demonstrated aclear dose dependence were then selected for secondary screening.

Secondary Screen

The goal of the secondary screening was to observe direct binding ofcompounds to ctRAGE. To form a compound-RAGE tail complex, the inventorsadded 5 uM of each compound dissolved in DMSO to 500 uL of 5 uMuniformly ¹⁵N-labeled RAGE tail in 10 mM potassium phosphate buffer, pH6.5. The changes caused by compound binding to RAGE tail were monitoredby using heteronuclear NMR experiment, ¹⁵N-HSQC. This experimentfacilitates monitoring chemical changes of backbone amide protons andnitrogens of RAGE tail due to compound binding (See below) [11].

The method used herein has been described by Rai et al. (J Biol Chem287, 5133-5144), the entire content of which is incorporated herein byreference.

High resolution NMR spectroscopy is widely used to screen small moleculelibraries. By using a technique called chemical shift perturbation, NMRspectroscopy provides a relatively fast and direct way toobserve/identify the binding epitopes of a protein for a small molecule.Each NMR active nucleus, ¹H, ¹³C and ¹⁵N, in a ¹³C and/or ¹⁵N-labeledprotein, exhibits a unique chemical shift that reflects its chemicalenvironment in the molecular structure, and is exquisitely sensitive tochanges in that environment caused by small molecule binding to theprotein. Standard NMR assignment procedures the inventors to determinethe chemical shifts for all NMR active nuclei in the protein ofinterest. Since changes in these chemical shifts reflect structuralchanges in the immediate vicinity of the small molecule binding site onthe protein, quantifying the changes and mapping affected amino acids onthe 3D protein structure unambiguously confirm the binding event andalso define the small molecule-protein interaction surface at atomicresolution.

NMR spectroscopy allows the inventors to estimate binding affinitiesdepending on the magnitude of the chemical shift change ΔΩ and the rateconstant, k_(off), between bound and free states. Chemical exchange canresult in gradual changes of chemical shifts when ΔΩ<<k_(off) (fastexchange), line broadening when ΔΩ≦k_(off) (intermediate exchange) orthe appearance of new peaks when ΔΩ>>k_(off) (slow exchange). Assumingthat the binding reaction is diffusion limited and the average change ofthe ¹H chemical shift is ˜0.1 ppm, the fast exchange regime will occurwhen the dissociation constant, K_(d), is larger than 100 uM andintermediate or slow exchange will occur when the dissociation constantis less than or equal to 10 uM. Binding stoichiometry can be establishedwhen no further changes in the chemical shifts or differentialbroadening of specific peaks in the NMR spectra occur as the molar ratioof small molecule to protein increases. The binding affinities can beestimated by using the complementary method of surface plasmon resonance(SPR) and/or fluorescence titration.

To distinguish ¹⁵N- and/or ¹³C-labeled protein NMR signals from thoseoriginating from a small molecule, the chemical shift perturbationtechnique employs a ¹⁵N and/or ¹³C edited experiment known asheteronuclear single quantum coherence (HSQC). Each peak in the HSQCspectrum corresponds to a ¹H—¹⁵N and/or ¹H—¹³C bond in the protein. A700 MHz NMR spectrometer equipped with an ultrasensitive cryoprobe isused to conduct the assays; the combination of high magnetic field and acryoprobe significantly improves the sensitivity of NMR experiments.

Procedure

There are two possible modes of blocking complex formation between RAGEtail and the FH1 domain of Dia-1: A small molecule binds either to RAGEtail or the FH1 domain and obstructs the RAGE tail-FH1 interactionsurface. RAGE tail is a small, 43 amino acid peptide. It is onlypartially folded. A solution structure of a N-terminal fragment of RAGEtail is determined by the inventors. The FH1 domain is a 260 amino acidfragment of Dia-1 containing multiple polyproline stretches. Accordingto the preliminary results, FH1 does not have a well-defined tertiarystructure. Based on our preliminary results, the ¹⁵N-HSQC spectra ofboth free ¹⁵N-CT-RAGE and the ¹⁵N-CT-RAGE-FH1 complex contain wellresolved peaks that have been assigned to facilitate chemical shiftperturbation screening. Thus, for the first round of the screen (FIG.2), the ¹⁵N-HSQC spectral changes of either free ¹⁵N-CT-RAGE or a¹⁵N-CT-RAGE-FH1 complex induced by small molecule binding are observed.The screenings are conducted by titrating up to 10 μM of a smallmolecule to 10 μM of the protein sample; small molecules that bind toCT-RAGE or FH1 with affinities weaker than 10 μM are unlikely be ofinterest for biological studies and are not pursued.

In general, if a small molecule binds to CT-RAGE then correspondingchanges in the ¹⁵N-HSQC spectrum of free ¹⁵N-CT-RAGE will be observed.

If a small molecule binds to the FH1 domain then no changes will beobserved in the ¹⁵N-HSQC spectrum of free ¹⁵N-CT-RAGE. However, specificchanges in the ¹⁵N-HSQC spectrum of ¹⁵N-CT-RAGE-FH1 will be observed.

At the titration endpoint, the ¹⁵N-HSQC spectrum of ¹⁵N-CT-RAGE-FH1 willbe similar to the spectrum of free ¹⁵N-CT-RAGE.

Binding affinities of small molecules for either CT-RAGE or FH1 aredetermined by performing fluorescence titrations to generate bindingisotherms and standard SPR experiments.

EXAMPLES

As detailed above, in order to identify small molecules to antagonizeRAGE activity, the present inventors developed primary screening assay.

From screening a chemical compounds library consisting of 59,000compounds, a number of compounds were identified as small moleculeinhibitors for the RAGE activity.

Example 1 Representative Method and Protocol for Primary Screening

Day 1

Step 1. Add 50 μl anti-mDia1 (1:160 dilution in 0.1M NaHCO₃ pH9.6)/well. Incubate overnight at 4° C.

Day 2

Step 2. Use the plate washer to aspirate anti-mDia1 and wash plates 4×with PBS 100 μl per well per wash.

Step 3. Add 180 μl 3% BSA in 1×PBS. Incubate for 1.5 hrs at roomtemperature

Step 4. Use the plate washer to aspirate the blocking solution and wash5× with PBS 300 μl per well.

Step 5. Add 50 μl of mDia1 containing lysate (85 μg) and incubate at RTfor 3 hours.

Step 6. Aspirate the lysate and wash the plate 5× (100 μl) on the platewasher.

Step 7. Add 25 μl PBS to the wells.

Step 8. Add 0.5 μL compound per well.

Step 9. Add 24.5 μL GFP RAGE tail (125 nM) into each well for 2 hrs atroom temperature.

Step 10. Aspirate and wash 5× with PBS (100 μL) on the plate washer.

Step 11. Add 100 ul PBS in each well.

Step 12. Detection: Read on fluorescence plate reader excitation 435 nmand 485 nm emission

Compounds that blocked the binding of RAGE tail to mDia1 by 50% or morewere subjected to 4 point dose response: 10 μM, 1 μM, 0.1 μM and 0.01μM.

Compounds that showed dose dependence were then subjected to secondaryscreen:

K_(d) Determinations

A number of representative amino and amido compounds of this inventionwere or can be tested for their inhibitory activity. The amino and amidocompounds of the invention along with their available K_(d) values, asdetermined using conventional methods to those skilled in the art, arelisted below in Table 1.

TABLE 1 Exemplary Amino, amido, and heterocyclic Compounds and availableK_(d) Values Compd MW K_(d) # Structure (Calcd) (nM) CB-1

288.37 4 ± 1 CB-5

304.32 1.1 ± 0.2 CB-6

325.78  0.1 ± 0.05 CB-7

339.32 0.55 ± 0.05 CB-8

387.39 2.0 ± 0.5  CB-13

320.75 123 ± 1   CB-14

278.15 1.4 ± 0.3 CD-1

31% Inhibition @ 10 μM  CD-21

18% Inhibition @ 10 μM  CD-42

42% Inhibition @ 10 μM

Compound#CB-1 was titrated into 100 nM solution of RAGE tail.Fluorescence quenching was used to determine binding. R2 quality factorof the fitting was 0.86 (FIG. 1).

Additional representative amido compounds according to formula A-I arelisted below in Table 2.

TABLE 2 Additional Representative Compounds ID STRUCTURE MW 201

261.30 202

275.33 203

275.33 204

289.36 205

303.39 206

289.36 207

317.41 208

303.34 209

306.30 210

337.40 211

351.43 212

351.43 213

319.34 214

365.46 215

365.46 216

362.41 217

351.43 218

338.39 219

355.39 220

367.43 221

371.85 222

338.39 223

379.48 224

387.46 225

379.48 226

383.49 227

394.46 228

365.46 229

343.43 230

338.39 231

385.88 232

351.43 233

413.50 234

351.43 235

381.46 236

365.46 237

393.51 238

365.46 239

379.48 240

377.47 241

379.48 242

371.85 243

355.39 244

347.40 245

367.43 246

391.50 247

373.38 248

395.48 249

389.84 250

365.46 251

379.48 252

379.44 253

399.90 254

406.29 255

381.46 256

346.41 257

379.48 258

372.49 259

406.29 260

373.38 261

401.87 262

372.49 263

405.40 264

376.44 265

339.80 266

347.40 267

387.41 268

395.48 269

420.32 270

397.46 271

394.46 272

361.42 273

397.46 274

395.44 275

385.42 276

406.47 277

359.41 278

429.59 279

399.90 280

383.45 281

379.44 282

375.45 283

412.32 284

370.77 285

401.87 286

453.87 287

396.52 288

411.87 289

444.56 290

429.93 291

411.87K_(d) Determinations

A number of representative heterocylic compounds of this invention wereor can be tested for their inhibitory activity. The heterocyliccompounds of the invention along with their available K_(d) values, asdetermined using conventional methods to those skilled in the art, arelisted below in Table 3.

TABLE 3 Exemplary Heterocylic compounds and available K_(d) Values CompdMW K_(d) # Structure (Calcd) (nM) CB-2

270.2  6.5 ± 1   CB-3

355.44 18 ± 1  CB-4

291.36 2 ± 1 CB-9

235.25 17.3 ± 0.5 μM CB-10

284.36 3.1 ± 0.3 CB-11

186.26 1.2 ± 0.5 CB-12

320.35 >100 μM CD-4

291.36 75 +/− 20 CD-6

371.44 4 +/− 2 CD-7

295.39 31% Inhibition @ 10 μM CD-8

293.33 27% Inhibition @ 10 μM CD-12

288.18 11% Inhibition @ 10 μM CD-14

282.35 26% Inhibition @ 10 μM CD-16

318.38 69% Inhibition @ 10 μM CD-18

343.43 45% Inhibition @ 10 μM CD-19

312.33 24% Inhibition @ 10 μM CD-20

301.41 48% Inhibition @ 10 μM CD-28

268.32 37% Inhibition @ 10 μM CD-29

305.38 78 +/− 50

Compound#CB-4 was titrated into 100 nM solution of RAGE tail.Fluorescence quenching was used to determine binding. R2 quality factorof the fitting was 0.87 (FIG. 5).

Additional representative heterocyclic compounds according to formulaB-I are listed below in Table 4.

TABLE 4 Additional Representative Compounds ID STRUCTURE MW 101

362.78 102

291.36 103

319.37 104

356.38 105

334.38 106

321.38 107

320.40 108

337.40 109

350.42 110

421.85 111

405.40 112

387.41 113

412.58 114

379.47 115

499.21 116

410.31 117

593.21 118

375.86 119

341.42 120

401.44 121

362.48 122

513.24 123

424.33 124

607.24 125

340.43 126

447.89 127

371.44 128

368.44 129

383.45 130

398.47 131

433.53 132

381.48 133

474.59 134

528.27 135

418.50 136

443.98 137

453.55 138

417.52 139

458.01 140

423.56 141

467.58 142

500.43 143

463.61 144

470.02 145

475.60 146

508.07 147

291.36 148

421.55 149

369.47 150

431.54 151

471.61 152

348.45

Example 2 Representative Method and Protocol for Secondary Screening

A complex of RAGE tail and a representative compound, CB-6, was preparedby adding 10 μM of CB-6 to a solution of 10 μM of [U—¹⁵N] RAGE tail in10 mM potassium phosphate buffer, pH 6.0. The NMR spectrum of thecomplex was acquired following the method described herein (FIG. 3). TheFIG. 3 shows overlay of ¹⁵N-HSQC spectra of free (red) and CB-6 bound[U—¹⁵N] RAGE tail (black). New peaks or peaks that undergo significantshifts are indicated by asteric and labeled by corresponding amino acidresidue numbers.

A complex of RAGE tail and a representative compound, CB-3, was preparedby adding 10 μM of CB-3 to a solution of 10 μM of [U—¹⁵N] RAGE tail in10 mM potassium phosphate buffer, pH 6.0. The NMR spectrum of thecomplex was acquired following the method described herein (FIG. 6). TheFIG. 6 shows overlay of ¹⁵N-HSQC spectra of free (red) and CB-3 bound[U—¹⁵N] RAGE tail (black). New peaks or peaks that undergo significantshifts or peak broadening are indicated by asteric and labeled bycorresponding amino acid residue numbers.

FIG. 7 presents a table that lists the dissociation constants determinedfor CB-1 to CB-14 binding to the RAGE tail.

Example 3 Representative In Vitro Assays

Methods and Materials

Effects of CB-1 to CB-14 on Murine Smooth Muscle Cell Migration. Primarymurine aortic smooth muscles retrieved from wild type C57BL/6 mice weregrown to 90% confluency in medium containing 10% fetal bovine serum.Cells were serum starved for 16 hrs during which time fetal bovine serumwas replaced with 0.1% bovine serum albumin. Following this period ofserum starvation, cells were pre-treated for 1.5 hours with theindicated Chembridge library hit denoted #1-14 at a concentration of 1μM. At the end of that time, compounds were removed and cell monolayerswere vertically scratched with a pipet tip to create a “wound” and thenRAGE ligand carboxy methyl lysine human serum albumin (CML AGE), 100μg/ml, was added for 7 hrs. Photographs of the monolayer were taken attime 0 (time of scratch/CML AGE) and at 7 hrs. The ingrowth of the cellswas then noted and % area ingrowth was calculated comparing ingrowth atbaseline to that at 7 hrs. N-triplicate experiments. * indicates p<0.05

Effects of CB-1 to CB-14 on Human Smooth Muscle Cell Migration. Primaryhuman aortic smooth muscles were purchased from Lonza and were grown to90% confluency in medium containing 10% fetal bovine serum. Cells wereserum starved for 16 hrs during which time fetal bovine serum wasreplaced with 0.1% bovine serum albumin. Following this period of serumstarvation, cells were pre-treated for 1.5 hours with the indicatedChembridge library hit denoted #1-14 at a concentration of 1 μM. At theend of that time, compounds were removed and cell monolayers werevertically scratched with a pipet tip to create a “wound” and then RAGEligand carboxy methyl lysine human serum albumin (CML AGE), 100 μg/ml,was added for 7 hrs. Photographs of the monolayer were taken at time 0(time of scratch/CML AGE) and at 7 hrs. The ingrowth of the cells wasthen noted and % area ingrowth was calculated comparing ingrowth atbaseline to that at 7 hrs. N=triplicate experiments. * indicates p<0.05(FIG. 8)

FIG. 8 shows that CB-2, CB-3, CB-4, CB-5, CB-6, CB-7, CB-8, CB-9, CB-10,CB-11, CB-12, CB-13, and CB-14 prevent RAGE ligand CML AGE-mediatedingrowth (migration) of primary murine aortic smooth muscle cells. Incontrast, CB-1 had no inhibitory effect. Rather, significantly higheringrowth in response to CML AGE was noted in the presence of CB-1. Theseresults indicate that CB compounds 2-14 suppress RAGE ligand-mediatedmigration/ingrowth of primary murine aortic smooth muscle cells.

FIG. 9 shows that CB-2, CB-3, CB-4, CB-5, CB-6, CB-7, CB-8, CB-9, CB-10,CB-11, CB-12, CB-13, and CB-14 prevent RAGE ligand CML AGE-mediatedingrowth (migration) of primary human aortic smooth muscle cells. Incontrast, CB-1 had no inhibitory effect on RAGE ligand-mediatedmigration/ingrowth of these cells. These results indicate that CBcompounds 2-14 suppress RAGE ligand-mediated migration/ingrowth ofprimary murine aortic smooth muscle cells.

Example 4 Representative In Vivo Assays

Methods and Materials

Effects of CB Compounds 1-14 on an in vivo model of delayed typehypersensitivity (DTH). Female CF-1 mice were purchased from the JacksonLaboratories (Bar Harbor Me.) and after a period of at least 3 daysacclimation in the animal facility, mice were sensitized over the leftinguinal lymph node with an emulsion (0.1 ml) containing methylatedbovine serum albumin (mBSA, Sigma, 25 mg/ml), NaCl (0.9%), dextran5-40×10⁶ MW; 50 mg/ml (Sigma), and Freunds' incomplete adjuvant (50%).On day 19 and 20 after sensitization, mice received an intraperitonealdose of one of CB compounds 1-14 at 5 mg/kg/body weight mouse for atotal of four doses. Control animals received equal volumes of compounddiluent, DMSO. Immediately following the final compound injection(4^(th) dose), mBSA (0.4 mg/ml; 0.050 ml) was injected into the leftplantar hind paw. The paw was scored 16 hrs later by 2 investigatorsnaive to the experimental condition and according to the followingcriteria: 1=absence of any inflammation; 2=slight rubor and edema;3=moderate rubor and edema with skin wrinkles; 4=severe rubor and edemawithout skin wrinkles and 5=severe rubor and edema with toe spreading.See also Hofmann et al. (1999, Cell 97:889-901), the entire content ofwhich is incorporated herein in its entirety. In these experiments, n=5mice/group.

As shown in FIG. 10 and in Table 5 (below), in a murine model of delayedtype hypersensitivity in which the pro-inflammatory ligands of RAGEaccumulate, CB compounds denoted as CB-3 and CB-12 impact astatistically significant reduction in inflammation score in the pawafter injection of methylated BSA compared to mice treated with vehicle,DMSO, and equal amounts of methylated BSA.

TABLE 5 Inflammation Score Compound # Compound/Vehicle ± SEM P Value Vs.Vehicle CB-1 3.4 ± 0.55/3.4 ± 0.55 Not Significant CB-2 3.2 ± 0.45/3.4 ±0.55 Not Significant CB-3 2.2 ± 0.45/3.4 ± 0.55 p = 0.0053 CB-4 3.0 ±0.71/3.4 ± 0.55 Not Significant CB-5 3.6 ± 0.55/3.4 ± 0.55 NotSignificant CB-6 3.0 ± 0.71/3.6 ± 0.55 Not Significant CB-7 3.4 ±0.55/3.6 ± 0.55 Not Significant CB-8 3.4 ± 0.55/3.6 ± 0.55 NotSignificant CB-9 3.6 ± 0.55/3.6 ± 0.55 Not Significant CB-10 3.2 ±0.84/3.6 ± 0.55 Not Significant CB-11 3.2 ± 0.45/3.4 ± 0.55 NotSignificant CB-12 2.4 ± 0.55/3.4 ± 0.55 p = 0.0203 CB-13 3.4 ± 0.55/3.4± 0.55 Not Significant CB-14 3.2 ± 0.45/3.4 ± 0.55 Not Significant

From the foregoing description, various modifications and changes in thecompositions and methods of this invention will occur to those skilledin the art. All such modifications coming within the scope of theappended claims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The chemical names of compounds of invention given in this applicationare generated using Open Eye Software's Lexichem naming tool, SymyxRenassance Software's Reaction Planner or MDL's ISIS Draw AutonomSoftware tool and not verified. Preferably, in the event ofinconsistency, the depicted structure governs.

REFERENCES

-   1) International Diabetes Federation. (2012) IDF Diabetes Atlas (5th    edn), International Diabetes Federation; Brussels, Belgium-   2) Patterson, C. C., et al. (2012) Trends in childhood type 1    diabetes incidence in Europe during 1989-2008: evidence of    non-uniformity over time in rates of increase. Diabetologia 55,    2142-2147-   3) Lipman, T. H., et al. (2013) Increasing Incidence of Type 1    Diabetes in Youth: Twenty years of the Philadelphia Pediatric    Diabetes Registry. Diabetes Care 36, 1597-1603-   4) Nathan D M, et al. (2009) Medical management of hyperglycemia in    type 2 diabetes: a consensus algorithm for the initiation and    adjustment of therapy: a consensus statement of the American    Diabetes Association and the European Association for the Study of    Diabetes. Diabetes Care 3: 193-203.-   5) (UKPDS), U.P.D.S.G. (1998) Intensive blood-glucose control with    sulphonylureas or insulin compared with conventional treatment and    risk of complications in patients with type 2 diabetes (UKPDS 33).    UK Prospective Diabetes Study (UKPDS) Group. Lancet, pp. 837-853-   6) The Diabetes Control and Complications Trial Research    Group (1993) The effect of intensive treatment of diabetes on the    development and progression of long-term complications in    insulin-dependent diabetes mellitus. The Diabetes Control and    Complications Trial Research Group. New Engl J Med, pp. 977-986-   7) Frye, E. B., et al. (1998) Role of the Maillard reaction in aging    of tissue proteins. Advanced glycation end product-dependent    increase in imidazolium cross-links in human lens proteins. J Biol    Chem 273, 18714-18719-   8) Yan, S. F., et al. (2009) Tempering the wrath of RAGE: an    emerging therapeutic strategy against diabetic complications,    neurodegeneration, and inflammation. Ann Med 41, 408-422-   9) Yan, S. F., et al. (2010) The RAGE axis: a fundamental mechanism    signaling danger to the vulnerable vasculature. Circ Res 106,    842-853-   10) Hudson, B. I., et al. (2008) Interaction of the RAGE cytoplasmic    domain with diaphanous-1 is required for ligand-stimulated cellular    migration through activation of Rac1 and Cdc42. J Biol Chem 283,    34457-34468-   11) Rai, V., et al. (2012) Signal transduction in receptor for    advanced glycation end products (RAGE): solution structure of    C-terminal rage (ctRAGE) and its binding to mDia1. J Biol Chem 287,    5133-5144-   12) Xu, Y., et al. (2010) Advanced glycation end product    (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1    in hypoxic macrophages. J Biol Chem 285, 23233-23240-   13) Toure, F., et al (2012) Formin mDia1 mediates vascular    remodeling via integration of oxidative and signal transduction    pathways. Circ Res 110, 1279-1293.

What is claimed is:
 1. A method for treating or ameliorating in a mammala disease or condition that is causally related to RAGE activity invivo, which comprises administering to the mammal an effectivedisease-treating or condition-treating amount of a compound according toformula B-I′:

wherein each A¹, A², A³, and A⁴ is independently CR⁴ or N; provided thatonly 1 or 2 of A¹, A², A³, and A⁴ are N at any one time; Z issubstituted amino, substituted hydroxyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; X is CR^(5a) or N; R¹is hydroxy, substituted hydroxyl, amino, or substituted amino; R² is H,alkyl or aryl; R^(3a) is H, substituted or unsubstitutedalkyl,substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, halo, or cyano; each R⁴ is independently selectedfrom H, OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted acyl, substituted orunsubstituted acylamino, substituted or unsubstituted alkylamino,substituted or unsubstituted alkythio, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkylarylamino, substitutedor unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo,substituted sulfo, substituted sulfonyl, substituted sulfinyl,substituted sulfanyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedarylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl,cyano, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituteddialkylamino, halo, nitro, and thiol; R^(5a) is independently H,substituted or unsubstituted alkyl,substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, halo, or cyano; or R^(5a)and R^(3a) may join together to form a substituted or unsubstitutedcarbocyclic or heterocyclic ring; and each of the subscript m and n isindependently 1, 2, or 3; or a pharmaceutically acceptable salt, solvateor prodrug thereof; or stereoisomers, isotopic variants and tautomersthereof; wherein the disease or condition is selected from diabetes andits complications, atherosclerosis, peripheral vascular disease andassociated complications, cardiovascular diseasenephropathy,retinopathy, cardio- and cerebrovascularischemia/reperfusion injury, heart attack, myocardial infarction,ischemic cardiomyopathy, cancer, tumor invasion and metastases, acuteand chronic inflammation, arthritis,allergy asthma, obesity,pollution-associated tissue or organ damage, infection, sepsis,pneumonia, liver injury/damage, amyloidoses, skin disorders, colitis,lupus, and impaired wound healing.
 2. The method according to claim 1,wherein Z is

wherein B¹, B², B³, and B⁴ is independently CR⁴ or N; Y is , CR^(5b) orNR^(5a); R^(3b) is R^(3a); and R⁴ are as in claim 1; and R^(5b) isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, halo, orcyano; or R^(5b) and R^(3b) may join together to form a substituted orunsubstituted carbocyclic or heterocyclic ring.
 3. The method accordingto claim 1, wherein the compound is according to formula B-I:

wherein each A¹, A², A³, A⁴, B¹, B², B³, and B⁴ is independently CR⁴ orN; provided that only 1 or 2 of A¹, A², A³, and A⁴ are N, and only 1 or2 of B¹, B², B³, and B⁴ are N at any one time; X is CR^(5a) or N; X isCR^(5b) or N; R¹ is hydroxy, substituted hydroxyl, amino, or substitutedamino; R² is H, alkyl or aryl; each R^(3a) and R^(3b) is independentlyH, substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, halo, or cyano; each R⁴is independently selected from H, OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; R^(5a) is independently H, substituted orunsubstituted alkyl,substituted or unsubstituted cycloalkyl, substitutedor unsubstituted aryl, halo, or cyano; or R^(5a) and R^(3a) may jointogether to form a substituted or unsubstituted carbocyclic orheterocyclic ring; R^(5b) is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, halo, or cyano; or R^(5b) and R^(3b)may join together to form a substituted or unsubstituted carbocyclic orheterocyclic ring; and each of the subscript m and n is independently 1,2, or 3; or a pharmaceutically acceptable salt, solvate or prodrugthereof; or stereoisomers, isotopic variants and tautomers thereof. 4.The method according to claim 1, wherein the compound is according toformula B-VII:

and wherein X, Y, R¹, R², R^(3a), R^(3b), m, and n are as in claim 3; ora pharmaceutically acceptable salt, solvate or prodrug thereof; orstereoisomers, isotopic variants and tautomers thereof.
 5. The methodaccording to claim 1, wherein the compound is according to formulaB-VIIIa, B-VIIIb, B-VIIIc, or B-VIIId:

and wherein R¹, R², R^(3a), R^(3b), R^(5a), R^(5b), m, and n are as inclaim 1; or a pharmaceutically acceptable salt, solvate or prodrugthereof; or stereoisomers, isotopic variants and tautomers thereof. 6.The method according to claim 1, wherein the compound is according toformula B-IXa, B-IXb, or B-IXc :

and wherein R¹, R², R^(3b), m, and n are as in claim 3; or apharmaceutically acceptable salt, solvate or prodrug thereof; orstereoisomers, isotopic variants and tautomers thereof.
 7. The methodaccording to claim 1, wherein R¹ is OH, alkoxy, or acyloxy.
 8. Themethod according claim 1, wherein R² is substituted or unsubstitutedalkyl.
 9. The method according to claim 1, wherein R² is substituted orunsubstituted aryl.
 10. The method according to claim 1, wherein m is 1;and n is
 1. 11. The method according to claim 1, wherein the compound isaccording to formula B-Xa, B-Xb, B-Xc, or B-Xd :

and wherein R^(3b) is as in claim 3; or a pharmaceutically acceptablesalt, solvate or prodrug thereof; or stereoisomers, isotopic variantsand tautomers thereof.
 12. The method according to claim 1, whereinR^(3b) is independently H, substituted or unsubstitutedalkyl,substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, halo, or cyano.
 13. The method according to claim 1,wherein the compound is according to formula B-XIa, B-XIb, B-XIc, B-XId,B-XIe, B-XIf, B-XIg, or B-XIh:

or a pharmaceutically acceptable salt, solvate or prodrug thereof; orstereoisomers, isotopic variants and tautomers thereof.
 14. The methodaccording to claim 1, wherein the compound is according to formulaB-XIIa, B-XIIb, B-XIIc, B-XIId, B-XIIe, or B-XIIf:

or a pharmaceutically acceptable salt, solvate or prodrug thereof; orstereoisomers, isotopic variants and tautomers thereof.
 15. The methodaccording to claim 1, wherein the compound is according to formulaB-XIIIa, B-XIIIb, B-XIIIc, or B-XIIId:

or a pharmaceutically acceptable salt, solvate or prodrug thereof; orstereoisomers, isotopic variants and tautomers thereof.
 16. The methodaccording to claim 1, wherein the compound is according to formulaB-XIVa, or B-XIVb:

or a pharmaceutically acceptable salt, solvate or prodrug orstereoisomers, isotopic variants and tautomers thereof.
 17. The methodaccording to claim 1, wherein the compound is according to formulaB-XVa, B-XVb, B-XVc, or B-XVd:

or a pharmaceutically acceptable salt, solvate or prodrug orstereoisomers, isotopic variants and tautomers thereof.
 18. The methodaccording to claim 1, wherein the compound is according to formulaB-XId, or B-XIIIa.
 19. The method of any one of claim 1, 2, or 3,wherein each R⁴ is independently selected from H, OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, Cl, F,nitro, and thiol.
 20. A method for treating or ameliorating in a mammala disease or condition that is causally related to RAGE activity invivo, which comprises administering to the mammal an effectivedisease-treating or condition-treating amount of a compound according toformula B-I′:

wherein each A¹, A², A³, and A⁴ is independently CR⁴ or N; provided thatonly 1 or 2 of A¹, A², A³, and A⁴ are N at any one time; Z is

B¹, B², B³, and B⁴ is independently CR⁴ or N; Y is CR^(5b) or NR^(5a);R^(3b) is R^(3a); R^(5b) is independently H, substituted orunsubstituted alkyl,substituted or unsubstituted cycloalkyl, substitutedor unsubstituted aryl, halo, or cyano; or R^(5b) and R^(3b) may jointogether to form a substituted or unsubstituted carbocyclic orheterocyclic ring; X is CR^(5a) or N; R¹ is hydroxy, substitutedhydroxyl, amino, or substituted amino; R² is H, alkyl or aryl; R^(3a) isH, substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, halo, or cyano; each R⁴is independently selected from H, OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, F, Cl,nitro, and thiol; R^(5a) is independently H, substituted orunsubstituted alkyl,substituted or unsubstituted cycloalkyl, substitutedor unsubstituted aryl, halo, or cyano; or R^(5a) and R^(3a) may jointogether to form a substituted or unsubstituted carbocyclic orheterocyclic ring; and each of the subscript m and n is independently 1,2, or 3; or a pharmaceutically acceptable salt, solvate or prodrugthereof; or stereoisomers, isotopic variants and tautomers thereof;wherein the disease or condition is selected from diabetes and itscomplications, atherosclerosis, peripheral vascular disease andassociated complications, cardiovascular disease, nephropathy,retinopathy, cardio- and cerebrovascular ischemia/reperfusion injury,heart attack, stroke, myocardial infarction, ischernic cardiomyopathy,cancer, tumor invasion and metastases, acute and chronic inflammation,arthritis, allergy, asthma, obesity, pollution-associated tissue ororgan damage, infection, sepsis, pneumonia, liver injury/damage,amyloidoses, skin disorders, skin aging, colitis, lupus, and impairedwound healing.
 21. The method according to claim 20, wherein thecompound is according to formula B-I:

wherein each A¹, A², A³, A⁴, B¹, B², B³, B⁴, R¹, R², R^(3a), R^(3b), R⁴,R^(5a), R^(5a), m, and n are as in claim 20; or a pharmaceuticallyacceptable salt, solvate or prodrug thereof; or stereoisomers, isotopicvariants and tautomers thereof.